SUBSTITUTED PHENOXY AMINOTHIAZOLONES as estrogen related receptor-alpha modulators

ABSTRACT

The present invention relates to compounds of Formula (I), 
     
       
         
         
             
             
         
       
     
     methods for preparing these compounds, compositions, intermediates and derivatives thereof and for treating a condition including but not limited to ankylosing spondylitis, artherosclerosis, arthritis (such as rheumatoid arthritis, infectious arthritis, childhood arthritis, psoriatic arthritis, reactive arthritis), bone-related diseases (including those related to bone formation), breast cancer (including those unresponsive to anti-estrogen therapy), cardiovascular disorders, cartilage-related disease (such as cartilage injury/loss, cartilage degeneration, and those related to cartilage formation), chondrodysplasia, chondrosarcoma, chronic back injury, chronic bronchitis, chronic inflammatory airway disease, chronic obstructive pulmonary disease, diabetes, disorders of energy homeostasis, gout, pseudogout, lipid disorders, metabolic syndrome, multiple myeloma, obesity, osteoarthritis, osteogenesis imperfecta, osteolytic bone metastasis, osteomalacia, osteoporosis, Paget&#39;s disease, periodontal disease, polymyalgia rheumatica, Reiter&#39;s syndrome, repetitive stress injury, hyperglycemia, elevated blood glucose level, and insulin resistance.

CROSS REFERENCE TO RELATED APPLICATION

This application claims the benefit of U.S. Provisional Application No.60/893,464, filed Mar. 7, 2007, which is incorporated by referenceherein.

FIELD OF THE INVENTION

The present invention relates to certain novel compounds, methods forpreparing compounds, compositions, intermediates and derivatives thereofand for treating conditions such as cancer, arthritis, inflammatoryairway disease, and metabolic disorders. More particularly, thecompounds of the present invention are Estrogen Related Receptor alpha(ERR-α) modulators useful for treating, ameliorating, preventing orinhibiting the progression of disease states, disorders, and conditionsmediated by ERR-α activity.

BACKGROUND OF THE INVENTION

Nuclear receptors are members of a superfamily of transcription factors.The members of this family share structural similarities and regulate adiverse set of biological effects (Olefsky, J. M. J. Biol. Chem. 2001,276(40), 36863-36864). Ligands activate or repress these transcriptionfactors that control genes involved in metabolism, differentiation andreproduction (Laudet, V. and H. Gronmeyer. The Nuclear ReceptorFactbooks. 2002, San Diego: Academic Press). Presently, the human genomeproject has identified about 48 members for this family and cognateligands have been identified for about 28 of them (Giguere, V. EndocrineRev. 1999, 20(5), 689-725). This protein family is composed of modularstructural domains that can be interchanged within the members of thefamily without loss of function. A typical nuclear receptor contains ahypervariable N-terminus, a conserved DNA binding domain (DBD), a hingeregion, and a conserved ligand-binding domain (LBD). The function of theDBD is targeting of the receptor to specific DNA sequences (NuclearHormone Receptor (NHR) response elements or NREs), and the function ofthe LBD is recognition of its cognate ligand. Within the sequence of thenuclear receptor there are regions involved in transcriptionalactivation. The Activation Function 1 (AF-1) domain is situated at theN-terminus and constitutively activates transcription (Rochette-Egly, C.et al. Cell 1997, 90, 97-107; Rochette-Egly, C. et al. Mol. Endocrinol.1992, 6, 2197-2209), while the Activation Function 2 (AF-2) domain isembedded within the LBD and its transcriptional activation is liganddependent (Wurtz, J. M. et al. Nat. Struct. Biol. 1996, 3, 87-94).Nuclear receptors can exist as monomers, homodimers or heterodimers andbind to direct or inverted nucleotide repeats (Laudet and Gronmeyer,2002; Aranda, A. and A. Pascual. Physiol. Rev. 2001, 81(3), 1269-1304).

The members of this family exist either in an activated or repressedbasal biological state. The basic mechanism of gene activation involvesligand dependent exchange of co-regulatory proteins. These co-regulatoryproteins are referred to as co-activators or co-repressors (McKenna, L.J. et al. Endocrine Rev. 1999, 20, 321-344). A nuclear receptor in therepressed state is bound to its DNA response element and is associatedwith co-repressor proteins that recruit histone de-acetylases (HDACs)(Jones, P. L. and Y. B. Shi. Curr. Top. Microbiol. Immunol. 2003, 274,237-268). In the presence of an agonist there is an exchange ofco-repressors with co-activators that in turn recruit transcriptionfactors that assemble into an ATP dependent chromatin-remodelingcomplex. Histones are hyper-acetylated, causing the nucleosome tounfold, and repression is alleviated. The AF-2 domain acts as the liganddependent molecular switch for the exchange of co-regulatory proteins.In the presence of an agonist the AF-2 domain undergoes a conformationaltransition and presents a surface on the LBD for interaction withco-activator proteins. In the absence of an agonist or in the presenceof an antagonist the AF-2 domain presents a surface that promotesinteractions with co-repressor proteins. The interaction surfaces on theLBD for both co-activators, and co-repressors overlap and provide aconserved molecular mechanism for gene activation or repression that isshared by the members of this family of transcription factors (Xu, H. E.et al. Nature 2002, 415 (6873), 813-817).

Natural ligands that modulate the biological activity of nuclearreceptors have been identified for only approximately one half of knownnuclear receptors. Receptors for which no natural ligand has beenidentified are termed “orphan receptors.” The discovery of ligands orcompounds that interact with an orphan receptor will accelerate theunderstanding of the role of the nuclear receptors in physiology anddisease and facilitate the pursuit of new therapeutic approachesEstrogenrelated receptors (ERRs) constitutes a sub-class of these receptorswhere no ligand has been identified.

ERR-α (also known as ERR-1), an orphan receptor, is the first of thethree identified members of the estrogen receptor related subfamily oforphan nuclear receptors (ERR-α, β, γ). The ERR subfamily is closelyrelated to the estrogen receptors (ER-α and ER-β). ERR-α and ERR-β werefirst isolated by a low stringency hybridization screen (Giguere, V. etal. Nature 1988, 331, 91-94) followed later with the discovery of ERR-γ(Hong, H. et al. J. Biol. Chem. 1999, 274, 22618-22626). The ERRs andERs share sequence similarity with the highest homology observed intheir DBDs, approximately 60%, and all interact with the classical DNAestrogen response element. Recent biochemical evidence suggested thatthe ERRs and ERs share target genes, including pS2, lactoferin,aromatase and osteopontin, and share co-regulator proteins (Giguere, V.Trends in Endocrinol. Metab. 2002,13, 220-225; Vanacker, J. M. et al.EMBO J. 1999, 18, 4270-4279; Kraus, R. J. et al. J. Biol. Chem. 2002,272, 24286-24834; Hong et al., 1999; Zhang, Z. and C. T. Teng. J. Biol.Chem. 2000, 275, 20387-20846). Therefore, one of the main functions ofERR is to regulate the response of estrogen responsive genes. The effectof the steroid hormone estrogen is primarily mediated in the breast,bone and endometrium. Thus, the identification of compounds that willinteract with ERRs should provide a benefit for the treatment of bonerelated disease, breast cancer and reproduction.

ERR-α is shown to be present both in normal and breast cancer tissue(Ariazi, E. A. et al. Cancer Res. 2002, 62, 6510-6518). It has beenreported that the main function of ERR-α in normal breast tissue is thatof a repressor for estrogen responsive genes. In breast cancers or celllines that are non-estrogen responsive (ER-α negative), ERR-α has beenreported to be in an activated state (Ariazi et al., 2002). Therefore,compounds that will interact with ERR-α may be useful agents for thetreatment of breast cancer that is ER-α negative and non-responsive toclassical anti-estrogenic therapy, or may be used as an adjunct agentfor anti-estrogen responsive breast cancers. These agents may act asantagonists by reducing the biological activity of ERR-α in theseparticular tissues.

Many post-menopausal women experience osteoporosis, a condition that isa result of the reduction of estrogen production. Reduction of estrogenlevels results in an increase of bone loss (Turner, R. T. et al.Endocrine Rev. 1994,15(3), 275-300). An anabolic effect on bonedevelopment has been observed on the administration of estrogens topostmenopausal patients with osteoporosis (Pacifici, R. J. Bone Miner.Res. 1996,11(8), 1043-1051) but the molecular mechanism is unknown sinceER-a and ER-b knock-out animals have minor skeletal defects, where theaction of estrogens is typically mediated (Korach, K. S. Science 1994,266,1524-1527; Windahl, S. H. et al. J. Clin. Invest. 1999,104(7),895-901). Expression of ERR-α in bone is regulated by estrogen(Bonnelye, E. et al. Mol. Endocrin. 1997, 11, 905-916; Bonnelye, E. etal. J. Cell Biol. 2001,153, 971-984). ERR-α is maintained throughoutosteoblast differentiation stages. Over-expression of ERR-α in ratcalvaria osteoblasts, an accepted model of bone differentiation, resultsin an increase of bone nodule formation, while treatment of rat calvariaosteoblasts with ERR-α antisense results in a decrease of bone noduleformation. ERR-α also regulates osteopontin, a protein believed to beinvolved in bone matrix formation. Therefore compounds that willmodulate ERR-α by increasing its activity can have an anabolic effectfor the regeneration of bone density and provide a benefit over currentapproaches that prevent bone loss, but have no anabolic effect. Suchcompounds can enhance the activity of the receptor by two possiblemechanisms: i) enhancing the association of the receptor with proteinsthat enhance its activity or improve the stability of the receptor; andii) increasing the intracellular concentrations of the receptor andconsequently increasing its activity. Conversely, with respect to bonediseases that are a result of abnormal bone growth, compounds that willinteract with ERR-α and decrease its biological activity may provide abenefit for the treatment of these diseases by retarding bone growth.Antagonism of the association of the receptor with co-activator proteinsdecreases the activity of the receptor.

ERR-α is also present in cardiac, adipose, and muscle tissue and forms atranscriptional active complex with the PGC-1 co-activator family,co-activators implicated with energy homeostasis, mitochondriabiogenesis, hepatic gluconeogenesis and in the regulation of genesinvolved in fatty acid beta-oxidation (Kamei, Y. et al. Proc. Natl.Acad. Sci. USA 2003,100(21), 12378-12383). ERR-α regulates theexpression of the medium chain acyl-CoA dehydrogenase promoter (MCAD).Medium chain acyl-CoA dehydrogenase is a gene involved in the initialreaction in fatty acid beta-oxidation. It is believed that in theadipose tissue ERR-α regulates energy expenditure through the regulationof MCAD (Sladek, R. et al. Mol. Cell. Biol. 1997, 17, 5400-5409; Vega,R. B. and D. P. Kelly. J. Biol. Chem. 1997, 272, 31693-31699). Inantisense experiments in rat calvaria osteoblasts, in addition to theinhibition of bone nodule formation, there was an increase in adipocytedifferentiation markers including aP2 and PPAR-γ (Bonnelye, E. et al.Endocrinology 2002,143, 3658-3670). Recently an ERR-α knockout model hasbeen described that exhibited reduced fat mass relative to the wild typeand DNA chip analysis data indicated alteration of the expression levelsof genes involved in adipogenesis and energy metabolism (Luo, J. et al.Mol. Cell. Biol. 2003, 23(22), 7947-7956). More recently it has beenshown that ERR-α regulates the expression of endothelial nitric oxidesynthase, a gene that has a protective mechanism againstarteriosclerosis (Sumi, D. and L. J. Ignarro. Proc Natl. Acad. Sci.2003, 100,14451-14456). The biochemical evidence supports theinvolvement of ERR-α in metabolic homeostasis and differentiation ofcells into adipocytes. Therefore, compounds interacting with ERR-α canaffect energy homeostasis and may therefore provide a benefit for thetreatment of obesity and metabolic syndrome related disease indications,including arteriosclerosis and diabetes (Grundy, S. M. et al.Circulation 2004,109(3), 433-438).

Lion Bioscience AG has disclosed the use of certain pyrazole derivativesas antagonists of ERR-α for treating cancer, osteoporosis, obesity,lipid disorders and cardiovascular disorders and for regulatingfertility (European Published Patent Application 1398029).

There is a continuing need for new ERR-α inverse agonists. There is alsoa need for ERR-α inverse agonists useful for the treatment of conditionsincluding but not limited to ankylosing spondylitis, artherosclerosis,arthritis (such as rheumatoid arthritis, infectious arthritis, childhoodarthritis, psoriatic arthritis, reactive arthritis), bone-relateddiseases (including those related to bone formation), breast cancer(including those unresponsive to anti-estrogen therapy), cardiovasculardisorders, cartilage-related disease (such as cartilage injury/loss,cartilage degeneration, and those related to cartilage formation),chondrodysplasia, chondrosarcoma, chronic back injury, chronicbronchitis, chronic inflammatory airway disease, chronic obstructivepulmonary disease, diabetes, disorders of energy homeostasis, gout,pseudogout, lipid disorders, metabolic syndrome, multiple myeloma,obesity, osteoarthritis, osteogenesis imperfecta, osteolytic bonemetastasis, osteomalacia, osteoporosis, Paget's disease, periodontaldisease, polymyalgia rheumatica, Reiter's syndrome, repetitive stressinjury, hyperglycemia, elevated blood glucose level, and insulinresistance.

SUMMARY OF THE INVENTION

In its many embodiments, the present invention provides novel compoundsuseful as, for example, ERR-α inverse agonists, methods of preparingsuch compounds, pharmaceutical compositions comprising one or more suchcompounds, methods of preparing pharmaceutical compositions comprisingone or more such compounds, and methods of treatment, prevention,inhibition or amelioration of one or more diseases associated with ERR-αusing such compounds or pharmaceutical compositions.

One aspect of the present invention features a compound of Formula (I)

wherein

X is S or O;

R₁ is halo, optionally substituted C₁₋₄alkyl, optionally substitutedC₁₋₄alkoxy, or hydroxyl;

R₂ is selected from halo substituted C₁₋₃alkyl, cyano, halo, —C(O)NH₂,and —C(O)O—C₁₋₄alkyl, or alternatively R₂ is linked together to R₃ toform an aryl fused to the phenyl ring to which R₂ and R₃ are shownattached;

R₃ is H, or alternatively R₃ is linked together to R₂ to form an arylfused to the phenyl ring to which R₃ and R₂ are shown attached;

R₄ is halo, cyano, halo substituted C₁₋₃alkyl, —C≡CH, —C(O)O—C₁₋₄alkyl,—C(O)NH₂, or —S(O₂)—C₁₋₄alkyl; and

R₅ and R₆ are independently selected from H, optionally substitutedC₁₋₄alkyl, optionally substituted heteroaryl, and optionally substitutedheterocyclyl, or alternatively R₅ and R₆ are linked together with the Natom to which they are attached to form an optionally substitutedN-containing heterocyclyl;

or an optical isomer, enantiomer, diastereomer, cis-trans isomer,racemate, prodrug or pharmaceutically acceptable salt thereof.

Another aspect of the present invention features a pharmaceuticalcomposition comprising at least one compound of Formula (I) and at leastone pharmaceutically acceptable carrier.

The present invention also features a method of treating a subjectsuffering from or diagnosed with a disease, disorder, or conditionmediated by ERR-α activity, comprising administering to the subject atherapeutically effective amount of at least one compound of Formula(I). Such disease, disorder, or condition can include, but is notlimited to ankylosing spondylitis, artherosclerosis, arthritis (such asrheumatoid arthritis, infectious arthritis, childhood arthritis,psoriatic arthritis, reactive arthritis), bone-related diseases(including those related to bone formation), breast cancer (includingthose unresponsive to anti-estrogen therapy), cardiovascular disorders,cartilage-related disease (such as cartilage injury/loss, cartilagedegeneration, and those related to cartilage formation),chondrodysplasia, chondrosarcoma, chronic back injury, chronicbronchitis, chronic inflammatory airway disease, chronic obstructivepulmonary disease, diabetes, disorders of energy homeostasis, gout,pseudogout, lipid disorders, metabolic syndrome, multiple myeloma,obesity, osteoarthritis, osteogenesis imperfecta, osteolytic bonemetastasis, osteomalacia, osteoporosis, Paget's disease, periodontaldisease, polymyalgia rheumatica, Reiter's syndrome, repetitive stressinjury, hyperglycemia, elevated blood glucose level, and insulinresistance. The therapeutically effective amount of the compound ofFormula (I) can be from about 0.1 mg/day to about 5000 mg/day.

The present invention further features a process for making apharmaceutical composition comprising admixing any of the compoundsaccording to Formula (I) and a pharmaceutically acceptable carrier.

Additional embodiments and advantages of the invention will becomeapparent from the detailed discussion, schemes, examples, and claimsbelow.

DETAILED DESCRIPTION OF THE INVENTION

This invention relates to novel ERR-α modulators and compositionsthereof for the treatment, amelioration, prevention or inhibition ofnumerous conditions, including but not limited to cancer, arthritis,inflammatory airway disease, bone-related diseases, metabolic disorders,and associated symptoms or complications thereof.

One aspect of the present invention features a compound of Formula (I)

wherein

X is S or O;

R₁ is halo, optionally substituted C₁₋₄alkyl, optionally substitutedC₁₋₄alkoxy, or hydroxyl;

R₂ is selected from halo substituted C₁₋₃alkyl, cyano, halo, —C(O)NH₂,and —C(O)O—C₁₋₄alkyl, or alternatively R₂ is linked together to R₃ toform an aryl fused to the phenyl ring to which R₂ and R₃ are shownattached;

R₃ is H, or alternatively R₃ is linked together to R₂ to form an arylfused to the phenyl ring to which R₃ and R₂ are shown attached;

R₄ is halo, cyano, halo substituted C₁₋₃alkyl, —C≡CH, —C(O)O—C₁₋₄alkyl,—C(O)NH₂, or —S(O₂)—C₁₋₄alkyl; and

R₅ and R₆ are independently selected from H, optionally substitutedC₁₋₄alkyl, optionally substituted heteroaryl, and optionally substitutedheterocyclyl, or alternatively R₅ and R₆ are linked together with the Natom to which they are attached to form an optionally substitutedN-containing heterocyclyl;

or an optical isomer, enantiomer, diastereomer, cis-trans isomer,racemate, prodrug or pharmaceutically acceptable salt thereof.

In particular, the present invention includes a cis-trans isomer of thecompound of Formula (I), which has the following structure, wherein X,R₁, R₂, R₃, R₄, R₅, and R₆ are as described above:

Particularly, R₁ is C₁₋₂alkoxy, F, Cl, or Br. More particularly, R₁ is—O—CH₃, F or Cl. Even more particularly, R₁ is —O—CH₃ or F.

Particularly, R₂ is CF₃ or Cl and R₃ is H, or alternatively R₂ is linkedtogether to R₃ to form an aryl fused to the phenyl ring to which R₂ andR₃ are shown attached. More particularly, R₂ is CF₃ or Cl and R₃ is H,or alternatively R₃ is linked together to R₂ to form a phenyl fused tothe phenyl ring to which R₃ and R₂ are shown attached.

In one embodiment, R₂ is linked together to R₃ to form a phenyl fused tothe phenyl ring to which R₂ and R₃ are shown attached. In anotherembodiment, R₂ is CF₃, Cl, or Br. In a further embodiment, R₂ is CF₃ orCl. More particularly, R₂ is CF₃.

More particularly, R₃ is H.

Particularly, R₄ is cyano and R₂ is CF₃ or Cl. More particularly, R₄ iscyano.

Particularly, X is S.

Particularly, R₅ and R₆ are independently selected from H and optionallysubstituted C₁₋₄alkyl, or alternatively R₅ and R₆ are linked togetherwith the N atom to which they are attached to form an optionallysubstituted N-containing heterocyclyl.

Particularly, R₅ is H and R₆ is optionally substituted C₁₋₄alkyl. In oneembodiment, R₅ is H and R₆ is H. In another embodiment, R₅ and R₆ areeach optionally substituted C₁₋₄alkyl. Further, R₅ and R₆ are linkedtogether with the N atom to which they are attached to form anoptionally substituted N-containing heterocyclyl.

More particularly, when R₅ or R₆ is optionally substituted C₁₋₄alkyl,the substituted C₁₋₄alkyl is independently selected from

Particularly, the present invention includes a compound of Formula (I)wherein

-   -   R₁ is C₁₋₂alkoxy, F, or Cl;    -   R₂ is CF₃ or Cl, or alternatively R₂ is linked together to R₃ to        form a phenyl fused to the phenyl ring to which R₂ and R₃ are        shown attached;    -   R₃ is H;    -   R₄ is cyano; and    -   X is S;        or an optical isomer, enantiomer, diastereomer, racemate,        cis-trans isomer, prodrug or pharmaceutically acceptable salt        thereof.

Compounds 1 and 4

Particularly, the present invention includes a compound of Formula (I)wherein

-   -   R₁ is C₁₋₂alkoxy, F, or Cl;    -   R₂ is CF₃ or Cl, or alternatively R₂ is linked together to R₃ to        form a phenyl fused to the phenyl ring to which R₂ and R₃ are        shown attached;    -   R₄ is cyano;    -   X is S; and    -   R₅ and R₆ are both H;

or an optical isomer, enantiomer, diastereomer, racemate, cis-transisomer, prodrug or pharmaceutically acceptable salt thereof.

Compounds 23, 41 and 50

Particularly, the present invention includes a compound of Formula (I)wherein

-   -   R₁ is C₁₋₂alkoxy, F, or Cl;    -   R₂ is CF₃ or Cl;    -   R₃ is H;    -   R₄ is cyano;    -   X is S; and    -   R₅ and R₆ are each optionally substituted C₁₋₄alkyl;

or an optical isomer, enantiomer, diastereomer, racemate, cis-transisomer, prodrug or pharmaceutically acceptable salt thereof.

Compounds 61 and 62

Particularly, the present invention includes a compound of Formula (I)wherein

-   -   R₁ is C₁₋₂alkoxy, F, or Cl;    -   R₂ is CF₃ or Cl;    -   R₃ is H;    -   R₄ is halo;    -   X is S; and    -   R₅ and R₆ are each optionally substituted C₁₋₄alkyl or        alternatively R₅ and R₆ are linked together with the N atom to        which they are attached to form an optionally substituted        N-containing heterocyclyl;

or an optical isomer, enantiomer, diastereomer, racemate, cis-transisomer, prodrug or pharmaceutically acceptable salt thereof.

Compounds 42, 49, 51, 74, 96, and 107

Particularly, the present invention includes a compound of Formula (I)wherein

-   -   R₁ is C₁₋₂alkoxy, F, or Cl;    -   R₂ is CF₃ or Cl;    -   R₃ is H;    -   R₄ is cyano;    -   X is S; and    -   R₅ is H and R₆ is optionally substituted C₁₋₄alkyl;

or an optical isomer, enantiomer, diastereomer, racemate, cis-transisomer, prodrug or pharmaceutically acceptable salt thereof.

Compounds 21, 47, 55, 94, 102, 106, and 116

Particularly, the present invention includes a compound of Formula (I)wherein

-   -   R₁ is C₁₋₂alkoxy, F, or Cl;    -   R₂ is CF₃ or Cl;    -   R₃ is H;    -   R₄ is cyano;    -   X is S; and    -   R₅ and R₆ are linked together with the N atom to which they are        attached to form an optionally substituted N-containing        heterocyclyl;

or an optical isomer, enantiomer, diastereomer, racemate, cis-transisomer, prodrug or pharmaceutically acceptable salt thereof.

Compound 52

In another embodiment, the present invention includes a compound ofFormula (I) wherein

-   -   R₁ is C₁₋₂alkoxy, F, or Cl;    -   R₂ is CF₃ or Cl;    -   R₃ is H;    -   R₄ is —C(O)O—C₁₋₄alkyl;    -   X is S; and    -   R₅ and R₆ are linked together with the N atom to which they are        attached to form an optionally substituted N-containing        heterocyclyl;

or an optical isomer, enantiomer, diastereomer, racemate, cis-transisomer, prodrug or pharmaceutically acceptable salt thereof.

Compound 58

In another embodiment, the present invention includes a compound ofFormula (I) wherein

-   -   R₁ is C₁₋₂alkoxy, F, or Cl;    -   R₂ is CF₃ or Cl;    -   R₃ is H;    -   R₄ is halo substituted C₁₋₃alkyl;    -   X is S; and    -   R₅ and R₆ are linked together with the N atom to which they are        attached to form an optionally substituted N-containing        heterocyclyl;

or an optical isomer, enantiomer, diastereomer, racemate, cis-transisomer, prodrug or pharmaceutically acceptable salt thereof.

More particularly, an example of the present invention includescompounds of Formula (I) wherein

R₁ is methoxy;

R₂ is CF₃;

R₃ is H; and

R₄ is cyano.

It is an embodiment of the present invention to provide a compoundselected from:

It another embodiment, the present invention provides a compoundselected from:

Another aspect of the present invention features a pharmaceuticalcomposition comprising at least one compound of Formula (I) and at leastone pharmaceutically acceptable carrier. Particularly, a pharmaceuticalcomposition of the present invention can further comprise at least oneadditional agent, drug, medicament, antibody and/or inhibitor fortreating, ameliorating or preventing an ERR-α mediated disease. Moreparticularly, a pharmaceutical composition of the present inventioncomprises a compound selected from:

More particularly, a pharmaceutical composition of the present inventioncomprises at least a compound selected from:

The present invention also features a method of treating a subjectsuffering from or diagnosed with a disease, disorder, or conditionmediated by ERR-α activity, comprising administering to the subject atherapeutically effective amount of at least one compound of Formula(I).

The present invention also features a method for preventing orinhibiting the progression of an ERR-α-mediated condition in a subjectin need thereof, comprising administering to said subject atherapeutically effective amount of at least one compound of Formula(I).

The present invention also features a method for treating a prediabeticcondition in a subject in need thereof, comprising administering to saidsubject a therapeutically effective amount of at least one compound ofFormula (I).

Such disease, disorder, or condition can include, but is not limited toankylosing spondylitis, artherosclerosis, arthritis (such as rheumatoidarthritis, infectious arthritis, childhood arthritis, psoriaticarthritis, reactive arthritis), bone-related diseases (including thoserelated to bone formation), breast cancer (including those unresponsiveto anti-estrogen therapy), cardiovascular disorders, cartilage-relateddisease (such as cartilage injury/loss, cartilage degeneration, andthose related to cartilage formation), chondrodysplasia, chondrosarcoma,chronic back injury, chronic bronchitis, chronic inflammatory airwaydisease, chronic obstructive pulmonary disease, diabetes, disorders ofenergy homeostasis, gout, pseudogout, lipid disorders, metabolicsyndrome, multiple myeloma, obesity, osteoarthritis, osteogenesisimperfecta, osteolytic bone metastasis, osteomalacia, osteoporosis,Paget's disease, periodontal disease, polymyalgia rheumatica, Reiter'ssyndrome, repetitive stress injury, hyperglycemia, elevated bloodglucose level, and insulin resistance.

According to one aspect of the invention, the disclosed compounds andcompositions are useful for the amelioration of symptoms associatedwith, the treatment of, and preventing and/or inhibiting the progressionof, the following conditions and diseases: bone-related disease, boneformation, cartilage formation, cartilage loss, cartilage degeneration,cartilage injury, ankylosing spondylitis, chronic back injury, gout,osteoporosis, osteolytic bone metastasis, multiple myeloma,chondrosarcoma, chondrodysplasia, osteogenesis imperfecta, osteomalacia,Paget's disease, polymyalgia rheumatica, pseudogout, arthritis,rheumatoid arthritis, infectious arthritis, osteoarthritis, psoriaticarthritis, reactive arthritis, childhood arthritis, Reiter's syndrome,and repetitive stress injury.

According to another aspect of the invention, the disclosed compoundsand compositions are useful for the amelioration of symptoms associatedwith, the treatment of, and preventing and/or inhibiting the progressionof, the following conditions and diseases: periodontal disease, chronicinflammatory airway disease, chronic bronchitis, and chronic obstructivepulmonary disease.

According to a further aspect of the invention, the disclosed compoundsand compositions are useful for the amelioration of symptoms associatedwith, the treatment of, and preventing and/or inhibiting the progressionof breast cancer.

According to yet another aspect of the invention, the disclosedcompounds and compositions are useful for the amelioration of symptomsassociated with, the treatment of, and preventing and/or inhibiting theprogression of, the following conditions and diseases: metabolicsyndrome, obesity, disorders of energy homeostasis, diabetes, lipiddisorders, cardiovascular disorders, artherosclerosis, hyperglycemia,elevated blood glucose level, and insulin resistance.

Particularly, a method of the present invention comprises administeringto the subject a therapeutically effective amount of (a) at least onecompound of Formula (I); and (b) at least one additional agent selectedfrom a second ERR-α inverse agonist, an ERR-α antagonist, a glucokinasemodulator, an anti-diabetic agent, an anti-obesity agent, a lipidlowering agent, an anti-thrombotic agent, direct thrombin inhibitor, anda blood pressure lowering agent, said administration being in any order.More particularly, the additional agent in (b) is a second ERR-α inverseagonist different from the compound in (a). More particularly, theadditional agent in (b) is an anti-obesity agent selected from CB1antagonists, monoamine reuptake inhibotors, and lipase inhibitors. Moreparticularly, the additional agent in (b) is selected from rimonabant,sibutramine, and orlistat.

The present invention also features a method for treating or inhibitingthe progression of one or more ERR-α-mediated conditions, said methodcomprising administering to a patient in need of treatment apharmaceutically effective amount of a composition of the invention.

It is a further embodiment of the invention to provide a process formaking a pharmaceutical composition comprising admixing any of thecompounds according to Formula (I) and a pharmaceutically acceptablecarrier.

The invention also features pharmaceutical compositions which include,without limitation, one or more of the disclosed compounds, andpharmaceutically acceptable carriers or excipients.

In a further embodiment of the invention, a method for treating orameliorating an ERR-α-mediated condition in a subject in need thereofcomprises administering to the subject a therapeutically effectiveamount of at least one compound of Formula (I), wherein thetherapeutically effective amount of the compound of Formula (I) is fromabout 0.1 mg/dose to about 5 g/dose. In particular, the therapeuticallyeffective amount of the compound of Formula (I) is from about 0.5mg/dose to about 1000 mg/dose. More particularly, the therapeuticallyeffective amount of the compound of Formula (I) is from about 1 mg/doseto about 100 mg/dose. In a further embodiment of the invention, thenumber of doses per day of a compound of Formula (I) is from 1 to 3doses. In a further embodiment of the invention, the therapeuticallyeffective amount of the compound of Formula (I) is from about 0.001mg/kg/day to about 30 mg/kg/day. More particularly, the therapeuticallyeffective amount of the compound of Formula (I) is from about 0.01mg/kg/day to about 2 mg/kg/day.

In a further embodiment of the invention, a method for preventing orinhibiting the progression of an ERR-α-mediated condition in a subjectin need thereof comprises administering to the subject a therapeuticallyeffective amount of at least one compound of Formula (I), wherein thetherapeutically effective amount of the compound of Formula (I) is fromabout 0.1 mg/dose to about 5 g/dose. In particular, the therapeuticallyeffective amount of the compound of Formula (I) is from about 1 mg/doseto about 100 mg/dose. In a further embodiment of the invention, thenumber of doses per day of a compound of Formula (I) is from 1 to 3doses. In a further embodiment of the invention, the therapeuticallyeffective amount of the compound of Formula (I) is from about 0.001mg/kg/day to about 30 mg/kg/day. More particularly, the therapeuticallyeffective amount of the compound of Formula (I) is from about 0.01mg/kg/day to about 2 mg/kg/day.

In yet another embodiment of the invention, a method for treating aprediabetic condition in a subject in need thereof, comprisesadministering to said subject a therapeutically effective amount of atleast one compound of Formula (I), wherein the therapeutically effectiveamount of the compound of Formula (I) is from about 0.1 mg/dose to about5 g/dose. In particular, the therapeutically effective amount of thecompound of Formula (I) is from about 1 mg/dose to about 100 mg/dose. Ina further embodiment of the invention, the number of doses per day of acompound of Formula (I) is from 1 to 3 doses. In a further embodiment ofthe invention, the therapeutically effective amount of the compound ofFormula (I) is from about 0.001 mg/kg/day to about 30 mg/kg/day. Moreparticularly, the therapeutically effective amount of the compound ofFormula (I) is from about 0.01 mg/kg/day to about 2 mg/kg/day.

The invention is further described below.

A) Terms

Some terms are defined below and by their usage throughout thisdisclosure.

Unless otherwise noted, “alkyl” as used herein, whether used alone or aspart of a substituent group, refers to a saturated, branched, orstraight-chain monovalent hydrocarbon radical derived by the removal ofone hydrogen atom from a single carbon atom of a parent alkane. Typicalalkyl groups include, but are not limited to, methyl; ethyls such asethanyl; propyls such as propan-1-yl, propan-2-yl, cyclopropan-1-yl.;butyls such as butan-1-yl, butan-2-yl, 2-methyl-propan-1-yl,2-methyl-propan-2-yl, cyclobutan-1-yl and the like. In preferredembodiments, the alkyl groups are C₁₋₆alkyl, with C₁₋₃ beingparticularly preferred. “Alkoxy” radicals are oxygen ethers formed fromthe previously described straight or branched chain alkyl groups. Insome embodiments, the alkyl or alkoxy are independently substituted withone to five, preferably one to three groups including, but not limitedto, oxo, amino, alkoxy, carboxy, heterocyclyl, hydroxyl, heteroaryl,cycloalkyl, CONH₂, NR′R″, NHCOR′, C(O)OR′, NHCON(R′)(R″), and halo (F,Cl, Br, or 1) wherein R′ and R″ are independently H or C₁₋₄ alkyl.

The term “cycloalkyl,” as used herein, refers to a stable, saturated orpartially saturated monocyclic or bicyclic ring system containing from 3to 8 ring carbons and preferably 5 to 7 ring carbons. Examples of suchcyclic alkyl rings include cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl or cycloheptyl. In some embodiments, the cycloalkyl issubstituted with one to five, preferably one to three groups including,but not limited to, amino, carboxy, oxo, hydroxyl, halo, heteroaryl(e.g., pyridyl, thiazole), and heterocyclyl (e.g., pyrrolidine,morpholine, piperazine, azepine).

The term “alkenyl” refers to an unsaturated branched, straight-chain orcyclic monovalent hydrocarbon radical, which has at least onecarbon-carbon double bond, derived by the removal of one hydrogen atomfrom a single carbon atom of a parent alkene. The radical may be ineither the cis or trans conformation about the double bond(s). Typicalalkenyl groups include, but are not limited to, ethenyl; propenyls suchas prop-1-en-1-yl, prop-1-en-2-yl, prop-2-en-1-yl, prop-2-en-2-yl,cycloprop-1-en-1-yl; cycloprop-2-en-1-yl; butenyls such asbut-1-en-1-yl, but-1-en-2-yl, 2-methyl-prop-1-en-1-yl, but-2-en-1-yl,but-2-en-1-yl, but-2-en-2-yl, buta-1,3-dien-1-yl, buta-1,3-dien-2-yl,cyclobut-1-en-1-yl, cyclobut-1-en-3-yl, cyclobuta-1,3-dien-1-yl, etc.;and the like. In some embodiments, the alkenyl is substituted with oneto five, preferably one to three groups including, but not limited to,oxo, amino, alkoxy, carboxy, heterocyclyl, hydroxyl, and halo.

The term “alkynyl” refers to an unsaturated branched, straight-chain orcyclic monovalent hydrocarbon radical, which has at least onecarbon-carbon triple bond, derived by the removal of one hydrogen atomfrom a single carbon atom of a parent alkyne. Typical alkynyl groupsinclude, but are not limited to, ethynyl; propynyls such asprop-1-yn-1-yl, prop-2-yn-1-yl, etc.; butynyls such as but-1-yn-1-yl,but-1-yn-3-yl, but-3-yn-1-yl, etc.; and the like. In some embodiments,the alkynyl is substituted with one to five, preferably one to threegroups including, but not limited to, oxo, amino, alkoxy, carboxy,heterocyclyl, hydroxyl, and halo.

The term “heteroaryl” refers to a monovalent heteroaromatic radicalderived by the removal of one hydrogen atom from a single atom of aparent heteroaromatic ring system. Typical heteroaryl groups includemonocyclic and bicyclic systems where one or both rings areheteroaromatic. Heteroaromatic rings may contain 1-4 heteroatomsselected from O, N, and S. Examples include but are not limited to,radicals derived from carbazole, imidazole, indazole, indole,indolizine, isoindole, isoquinoline, isothiazole, isoxazole,naphthyridine, oxadiazole, oxazole, purine, pyrazine, pyrazole,pyridazine, pyridine, pyrimidine, pyrrole, pyrrolizine, quinazoline,quinoline, quinolizine, quinoxaline, tetrazole, thiadiazole, thiazole,thiophene, triazole, xanthene, and the like. In some embodiments,“heteroaryl” is substituted. For instance, “heteroaryl” can besubstituted with, e.g., optionally substituted C₁₋₆alkyl, C₂₋₆alkenyl,C₂₋₆alkynyl, halo, hydroxyl, —CN, —C(O)OH, —C(O)O—C₁₋₄alkyl,—C(O)NR′R″—OR′, —SR′—C(O)R′, —N(R′)(R″), —S(O)₂—R′, and—S(O)₂—N(R′)(R″), wherein R′ and R″ are independently selected from H,C₁₋₆-alkyl, aryl, heteroaryl, and/or heterocyclyl.

The term “aryl,” as used herein, refers to aromatic groups comprising astable six-membered monocyclic, or ten-membered bicyclic orfourteen-membered tricyclic aromatic ring system which consists ofcarbon atoms. Examples of aryl groups include, but are not limited to,phenyl or naphthalenyl. In some embodiments, “aryl” is substituted. Forinstance, “aryl” can be substituted with, e.g., optionally substitutedC₁₋₆alkyl, C₁₋₆alkenyl, C₁₋₆alkynyl, halo, hydroxyl, —CN, —C(O)OH,—C(O)O—C₁₋₄alkyl, —C(O)NR′R″—OR′, —SR′—C(O)R′, —N(R′)(R″), —S(O)₂—R′,and —S(O)₂—N(R′)(R″), wherein R′ and R″ are independently selected fromH, C₁₋₆-alkyl, aryl, heteroaryl, and/or heterocyclyl.

The term “heterocyclyl” or “heterocycle” is a 3- to 8-member saturated,or partially saturated single or fused ring system which consists ofcarbon atoms and from 1 to 6 heteroatoms selected from N, O and S. Theheterocyclyl group may be attached at any heteroatom or carbon atomwhich results in the creation of a stable structure. Example ofheterocyclyl groups include, but are not limited to, 2-imidazoline,imidazolidine; morpholine, oxazoline, 2-pyrroline, 3-pyrroline,pyrrolidine, pyridone, pyrimidone, piperazine, piperidine, indoline,tetrahydrofuran, 2-pyrroline, 3-pyrroline, 2-imidazoline, 2-pyrazoline,and indolinone. In some embodiments, “heterocyclyl” or “heterocycle” areindependently substituted. For instance, “heterocyclyl” or “heterocycle”can be substituted with, e.g., optionally substituted C₁₋₆alkyl,C₁₋₆alkenyl, C₁₋₆alkynyl, halo, oxo, hydroxyl, —CN, —C(O)OH,—C(O)O—C₁₋₄alkyl, —C(O)NR′R″—OR′, —SR′—C(O)R′, —N(R′)(R″), —S(O)₂—R′,and —S(O)₂—N(R′)(R″), wherein R′ and R″ are independently selected fromH, C₁₋₆-alkyl, aryl, heteroaryl, and/or heterocyclyl.

The term “oxo” whether used alone or as part of a substituent grouprefers to an O═ to either a carbon or a sulfur atom. For example,phthalimide and saccharin are examples of compounds with oxosubstituents.

The term “cis-trans isomer” refers to stereoisomeric olefins orcycloalkanes (or hetero-analogues) which differ in the positions ofatoms (or groups) relative to a reference plane: in the cis-isomer theatoms are on the same side; in the trans-isomer they are on oppositesides.

The term “substituted” refers to a radical in which one or more hydrogenatoms are each independently replaced with the same or differentsubstituent(s).

With reference to substituents, the term “independently” means that whenmore than one of such substituent is possible, such substituents may bethe same or different from each other.

The term “composition” is intended to encompass a product comprising thespecified ingredients in the specified amounts, as well as any productwhich results, directly or indirectly, from combinations of thespecified ingredients in the specified amounts.

The term “subject” as used herein, refers to an animal, preferably amammal, most preferably a human, who is the object of treatment,observation or experiment.

It is intended that the definition of any substituent or variable at aparticular location in a molecule be independent of its definitionselsewhere in that molecule. It is understood that substituents andsubstitution patterns on the compounds of this invention can be selectedby one of ordinary skill in the art to provide compounds that arechemically stable and that can be readily synthesized by techniquesknown in the art as well as those methods set forth herein.

The term “inverse agonist” as used herein refers to compounds orsubstances that have the ability to decrease the constitutive level ofreceptor activation in the absence of an agonist instead of onlyblocking the activation induced by agonist binding at the receptor.

Metabolic disorders, diseases, or conditions include, but are notlimited to, diabetes, obesity, and associated symptoms or complicationsthereof. They include such conditions as IDDM (insulin-dependentdiabetes mellitus), NIDDM (non insulin-dependent diabetes mellitus), IGT(Impaired Glucose Tolerance), IFG (Impaired Fasting Glucose), Syndrome X(or Metabolic Syndrome), hyperglycemia, elevated blood glucose level,and insulin resistance. A condition such as IGT or IFG is also known asa “prediabetic condition” or “prediabetic state.”

Methods are known in the art for determining effective doses fortherapeutic and prophylactic purposes for the disclosed pharmaceuticalcompositions or the disclosed drug combinations, whether or notformulated in the same composition. For therapeutic purposes, the term“therapeutically effective amount” as used herein, means that amount ofeach active compound or pharmaceutical agent, alone or in combination,that elicits the biological or medicinal response in a tissue system,animal or human that is being sought by a researcher, veterinarian,medical doctor or other clinician, which includes alleviation of thesymptoms of the disease or disorder being treated. For prophylacticpurposes (i.e., inhibiting the progression of a disorder), the term“therapeutically effective amount” refers to that amount of each activecompound or pharmaceutical agent, alone or in combination, that treatsor inhibits in a subject the progression of a disorder as being soughtby a researcher, veterinarian, medical doctor or other clinician. Thus,the present invention provides combinations of two or more drugswherein, for example, (a) each drug is administered in an independentlytherapeutically or prophylactically effective amount; (b) at least onedrug in the combination is administered in an amount that issub-therapeutic or sub-prophylactic if administered alone, but istherapeutic or prophylactic when administered in combination with thesecond or additional drugs according to the invention; or (c) both (ormore) drugs are administered in an amount that is sub-therapeutic orsub-prophylactic if administered alone, but are therapeutic orprophylactic when administered together.

The term “pharmaceutically acceptable salt” refers to non-toxicpharmaceutically acceptable salts (Ref. International J. Pharm., 1986,33, 201-217; J. Pharm. Sci., 1997 (January), 66, 1, 1). Other salts wellknown to those in the art may, however, be useful in the preparation ofcompounds according to this invention or of their pharmaceuticallyacceptable salts. Representative organic or inorganic acids include, butare not limited to, hydrochloric, hydrobromic, hydriodic, perchloric,sulfuric, nitric, phosphoric, acetic, propionic, glycolic, lactic,succinic, maleic, fumaric, malic, tartaric, citric, benzoic, mandelic,methanesulfonic, hydroxyethanesulfonic, benzenesulfonic, oxalic, pamoic,2-naphthalenesulfonic, p-toluenesulfonic, cyclohexanesulfamic,salicylic, saccharinic or trifluoroacetic acid. Representative organicor inorganic bases include, but are not limited to, basic or cationicsalts such as benzathine, chloroprocaine, choline, diethanolamine,ethylenediamine, meglumine, procaine, aluminum, calcium, lithium,magnesium, potassium, sodium and zinc.

B) Compounds

Representative compounds of the present invention are listed in Table Ibelow:

TABLE I STRUCTURE COMPOUND # NAME

14-[4-(2-Amino-4-oxo-4H-thiazol-5-ylidenemethyl)-2-methoxy-phenoxy]-3-trifluoromethyl-benzonitrile

24-[4-(2-Amino-4-oxo-4H-thiazol-5-ylidenemethyl)-2-methoxy-phenoxy]-3-chloro-benzonitrile

34-[2-Chloro-4-(2-imino-4-oxo-thiazolidin-5-ylidenemethyl)-phenoxy]-3-trifluoromethyl-benzonitrile

44-[2-Fluoro-4-(2-imino-4-oxo-thiazolidin-5-ylidenemethyl)-phenoxy]-naphthalene-1-carbonitrile

54-[2-Methoxy-4-(2-morpholin-4-yl-4-oxo-4H-thiazol-5-ylidenemethyl)-phenoxy]-3-trifluoromethyl-benzonitrile

64-[2-Fluoro-4-(2-morpholin-4-yl-4-oxo-4H-thiazol-5-ylidenemethyl)-phenoxy]-3-trifluoromethyl-benzonitrile

74-{2-Methoxy-4-[2-(4-methyl-piperazin-1-yl)-4-oxo-4H-thiazol-5-ylidenemethyl]-phenoxy}-3-trifluoromethyl-benzonitrile

84-{2-Fluoro-4-[2-(4-methyl-piperazin-1-yl)-4-oxo-4H-thiazol-5-ylidenemethyl]-phenoxy}-3-trifluoromethyl-benzonitrile

94-[4-(2-Cyclopropylamino-4-oxo-4H-thiazol-5-ylidenemethyl)-2-methoxy-phenoxy]-3-trifluoromethyl-benzonitrile

104-[4-(2-Cyclopropylamino-4-oxo-4H-thiazol-5-ylidenemethyl)-2-fluoro-phenoxy]-3-trifluoromethyl-benzonitrile

114-(4-{2-[(2-Dimethylamino-ethyl)-methyl-amino]-4-oxo-4H-thiazol-5-ylidenemethyl}-2-methoxy-phenoxy)-3-trifluoromethyl-benzonitrile

124-(4-{2-[Bis-(2-hydroxy-ethyl)-amino]-4-oxo-4H-thiazol-5-ylidenemethyl}-2-methoxy-phenoxy)-3-trifluoromethyl-benzonitrile

134-{2-Methoxy-4-[4-oxo-2-(pyrrolidin-3-ylamino)-4H-thiazol-5-ylidenemethyl]-phenoxy}-3-trifluoromethyl-benzonitrile

144-{2-Methoxy-4-[2-(1-methyl-piperidin-4-ylamino)-4-oxo-4H-thiazol-5-ylidenemethyl]-phenoxy}-3-trifluoromethyl-benzonitrile

154-{2-Methoxy-4-[4-oxo-2-(tetrahydro-pyran-4-ylamino)-4H-thiazol-5-ylidenemethyl]-phenoxy}-3-trifluoromethyl-benzonitrile

164-(4-{2-[4-(2-Hydroxy-ethyl)-piperazin-1-yl]-4-oxo-4H-thiazol-5-ylidenemethyl}-2-methoxy-phenoxy)-3-trifluoromethyl-benzonitrile

174-(2-Methoxy-4-{4-oxo-2-[(pyridin-2-ylmethyl)-amino]-4H-thiazol-5-ylidenemethyl}-phenoxy)-3-trifluoromethyl-benzonitrile

184-{2-Methoxy-4-[2-(2-methoxy-ethylamino)-4-oxo-4H-thiazol-5-ylidenemethyl]-phenoxy}-3-trifluoromethyl-benzonitrile

194-(2-Methoxy-4-{4-oxo-2-[(pyridin-3-ylmethyl)-amino]-4H-thiazol-5-ylidenemethyl}-phenoxy)-3-trifluoromethyl-benzonitrile

204-{2-Methoxy-4-[4-oxo-2-(2-pyrrolidin-1-yl-ethylamino)-4H-thiazol-5-ylidenemethyl]-phenoxy}-3-trifluoromethyl-benzonitrile

214-{2-Methoxy-4-[4-oxo-2-(3-oxo-piperazin-1-yl)-4H-thiazol-5-ylidenemethyl]-phenoxy}-3-trifluoromethyl-benzonitrile

224-(2-Methoxy-4-{4-oxo-2-[3-(2-oxo-pyrrolidin-1-yl)-propylamino]-4H-thiazol-5-ylidenemethyl}-phenoxy)-3-trifluoromethyl-benzonitrile

234-(4-{2-[(2,3-Dihydroxy-propyl)-methyl-amino]-4-oxo-4H-thiazol-5-ylidenemethyl}-2-methoxy-phenoxy)-3-trifluoromethyl-benzonitrile

244-(2-Methoxy-4-{4-oxo-2-[(pyridin-4-ylmethyl)-amino]-4H-thiazol-5-ylidenemethyl}-phenoxy)-3-trifluoromethyl-benzonitrile

254-{2-Methoxy-4-[4-oxo-2-(2-piperidin-1-yl-ethylamino)-4H-thiazol-5-ylidenemethyl]-phenoxy}-3-trifluoromethyl-benzonitrile

264-{4-[2-(3-Dimethylamino-propylamino)-4-oxo-4H-thiazol-5-ylidenemethyl]-2-methoxy-phenoxy}-3-trifluoromethyl-benzonitrile

274-{2-Methoxy-4-[2-(3-morpholin-4-yl-propylamino)-4-oxo-4H-thiazol-5-ylidenemethyl]-phenoxy}-3-trifluoromethyl-benzonitrile

284-{2-Methoxy-4-[4-oxo-2-(2-pyridin-4-yl-ethylamino)-4H-thiazol-5-ylidenemethyl]-phenoxy}-3-trifluoromethyl-benzonitrile

294-{2-Methoxy-4-[4-oxo-2-(2-pyridin-3-yl-ethylamino)-4H-thiazol-5-ylidenemethyl]-phenoxy}-3-trifluoromethyl-benzonitrile

304-{2-Methoxy-4-[4-oxo-2-(2-pyrazol-1-yl-ethylamino)-4H-thiazol-5-ylidenemethyl]-phenoxy}-3-trifluoromethyl-benzonitrile

314-{4-[2-(4-Acetyl-piperazin-1-yl)-4-oxo-4H-thiazol-5-ylidenemethyl]-2-methoxy-phenoxy}-3-trifluoromethyl-benzonitrile

324-{4-[2-(2-Hydroxy-ethylamino)-4-oxo-4H-thiazol-5-ylidenemethyl]-2-methoxy-phenoxy}-3-trifluoromethyl-benzonitrile

334-{2-Methoxy-4-[2-(2-morpholin-4-yl-ethylamino)-4-oxo-4H-thiazol-5-ylidenemethyl]-phenoxy}-3-trifluoromethyl-benzonitrile

344-{4-[2-(2R,3-Dihydroxy-propylamino)-4-oxo-4H-thiazol-5-ylidenemethyl]-2-methoxy-phenoxy}-3-trifluoromethyl-benzonitrile

354-{4-[2-(2S,3-Dihydroxy-propylamino)-4-oxo-4H-thiazol-5-ylidenemethyl]-2-methoxy-phenoxy}-3-trifluoromethyl-benzonitrile

364-(2-Methoxy-4-{4-oxo-2-[2-(2-oxo-pyrrolidin-1-yl)-ethylamino]-4H-thiazol-5-ylidenemethyl}-phenoxy)-3-trifluoromethyl-benzonitrile

374-(4-{2-[(2-Amino-ethyl)-methyl-amino]-4-oxo-4H-thiazol-5-ylidenemethyl}-2-methoxy-phenoxy)-3-trifluoromethyl-benzonitrile

384-{4-[2-(4-Ethanesulfonyl-piperazin-1-yl)-4-oxo-4H-thiazol-5-ylidenemethyl]-2-methoxy-phenoxy}-3-trifluoromethyl-benzonitrile

394-{4-[2-(3-Hydroxy-pyrrolidin-1-yl)-4-oxo-4H-thiazol-5-ylidenemethyl]-2-methoxy-phenoxy}-3-trifluoromethyl-benzonitrile

404-{4-[2-(2,6-Dimethyl-morpholin-4-yl)-4-oxo-4H-thiazol-5-ylidenemethyl]-2-methoxy-phenoxy}-3-trifluoromethyl-benzonitrile

414-(4-{2-[Bis-(2-hydroxy-ethyl)-amino]-4-oxo-4H-thiazol-5-ylidenemethyl}-2-fluoro-phenoxy)-3-trifluoromethyl-benzonitrile

424-{2-Fluoro-4-[4-oxo-2-(2-[1,2,4]triazol-1-yl-ethylamino)-4H-thiazol-5-ylidenemethyl]-phenoxy}-3-trifluoromethyl-benzonitrile

434-{2-Fluoro-4-[2-(4-methyl-3-oxo-piperazin-1-yl)-4-oxo-4H-thiazol-5-ylidenemethyl]-phenoxy}-3-trifluoromethyl-benzonitrile

444-{4-[2-(4-Ethanesulfonyl-piperazin-1-yl)-4-oxo-4H-thiazol-5-ylidenemethyl]-2-fluoro-phenoxy}-3-trifluoromethyl-benzonitrile

454-{2-Fluoro-4-[2-(3-hydroxy-pyrrolidin-1-yl)-4-oxo-4H-thiazol-5-ylidenemethyl]-phenoxy}-3-trifluoromethyl-benzonitrile

464-{4-[2-(2,6-Dimethyl-morpholin-4-yl)-4-oxo-4H-thiazol-5-ylidenemethyl]-2-fluoro-phenoxy}-3-trifluoromethyl-benzonitrile

474-{2-Fluoro-4-[4-oxo-2-(3-oxo-piperazin-1-yl)-4H-thiazol-5-ylidenemethyl]-phenoxy}-3-trifluoromethyl-benzonitrile

484-{4-[2-(3-Dimethylamino-propylamino)-4-oxo-4H-thiazol-5-ylidenemethyl]-2-fluoro-phenoxy}-3-trifluoromethyl-benzonitrile

494-{2-Fluoro-4-[2-(3-morpholin-4-yl-propylamino)-4-oxo-4H-thiazol-5-ylidenemethyl]-phenoxy}-3-trifluoromethyl-benzonitrile

504-(4-{2-[(2,3-Dihydroxy-propyl)-methyl-amino]-4-oxo-4H-thiazol-5-ylidenemethyl}-2-fluoro-phenoxy)-3-trifluoromethyl-benzonitrile

514-(2-Fluoro-4-{4-oxo-2-[3-(2-oxo-pyrrolidin-1-yl)-propylamino]-4H-thiazol-5-ylidenemethyl}-phenoxy)-3-trifluoromethyl-benzonitrile

521-{5-[3-Methoxy-4-(4-methoxycarbonyl-2-trifluoromethyl-phenoxy)-benzylidene]-4-oxo-4,5-dihydro-thiazol-2-yl}-azetidine-3-carboxylicacid

534-{4-[2-(3-Hydroxy-piperidin-1-yl)-4-oxo-4H-thiazol-5-ylidenemethyl]-2-methoxy-phenoxy}-3-trifluoromethyl-benzoicacid methyl ester

544-{2-Methoxy-4-[4-oxo-2-(3-oxo-piperazin-1-yl)-4H-thiazol-5-ylidenemethyl]-phenoxy}-3-trifluoromethyl-benzoicacid methylester

551-{5-[4-(4-Cyano-2-trifluoromethyl-phenoxy)-3-ethoxy-benzylidene]-4-oxo-4,5-dihydro-thiazol-2-yl}-azetidine-3-carboxylicacid

564-(4-{2-[Bis-(2-hydroxy-ethyl)-amino]-4-oxo-4H-thiazol-5-ylidenemethyl}-2-ethoxy-phenoxy)-3-trifluoromethyl-benzonitrile

574-{2-Ethoxy-4-[4-oxo-2-(3-oxo-piperazin-1-yl)-4H-thiazol-5-ylidenemethyl]-phenoxy}-3-trifluoromethyl-benzonitrile

585-[4-(2,4-Bis-trifluoromethyl-phenoxy)-3-methoxy-benzylidene]-2-(3-hydroxy-piperidin-1-yl)-thiazol-4-one

594-{5-[4-(2,4-Bis-trifluoromethyl-phenoxy)-3-methoxy-benzylidene]-4-oxo-4,5-dihydro-thiazol-2-yl}-piperazin-2-one

605-[4-(4-Chloro-2-trifluoromethyl-phenoxy)-3-methoxy-benzylidene]-2-[2-(2-oxo-pyrrolidin-1-yl)-ethylamino]-thiazol-4-one

614-{5-[4-(4-Chloro-2-trifluoromethyl-phenoxy)-3-methoxy-benzylidene]-4-oxo-4,5-dihydro-thiazol-2-yl}-piperazin-2-one

625-[4-(4-Chloro-2-trifluoromethyl-phenoxy)-3-methoxy-benzylidene]-2-[(2,3-dihydroxy-propyl)-methyl-amino]-thiazol-4-one

633-Chloro-4-(2-methoxy-4-{4-oxo-2-[2-(2-oxo-pyrrolidin-1-yl)-ethylamino]-4H-thiazol-5-ylidenemethyl}-phenoxy)-benzonitrile

643-Chloro-4-{2-methoxy-4-[4-oxo-2-(3-oxo-piperazin-1-yl)-4H-thiazol-5-ylidenemethyl]-phenoxy}-benzonitrile

653-Chloro-4-(4-{2-[(2,3-dihydroxy-propyl)-methyl-amino]-4-oxo-4H-thiazol-5-ylidenemethyl}-2-methoxy-phenoxy)-benzonitrile

664-{5-[4-(4-Chloro-2-trifluoromethyl-phenoxy)-3-fluoro-benzylidene]-4-oxo-4,5-dihydro-thiazol-2-yl}-piperazin-2-one

675-[4-(4-Chloro-2-trifluoromethyl-phenoxy)-3-fluoro-benzylidene]-2-[3-(2-oxo-pyrrolidin-1-yl)-propylamino]-thiazol-4-one

682-{5-[4-(4-Cyano-2-trifluoromethyl-phenoxy)-3-methoxy-benzylidene]-4-oxo-4,5-dihydro-thiazol-2-ylamino}-3-hydroxy-propionicacid methyl ester

694-(4-{2-[2-(2-Hydroxy-ethoxy)-ethylamino]-4-oxo-4H-thiazol-5-ylidenemethyl}-2-methoxy-phenoxy)-3-trifluoromethyl-benzonitrile

704-{4-[2-(2-Imidazol-1-yl-ethylamino)-4-oxo-4H-thiazol-5-ylidenemethyl]-2-methoxy-phenoxy}-3-trifluoromethyl-benzonitrile

71N-(2-{5-[4-(4-Cyano-2-trifluoromethyl-phenoxy)-3-methoxy-benzylidene]-4-oxo-4,5-dihydro-thiazol-2-ylamino}-ethyl)-acetamide

724-{2-Methoxy-4-[4-oxo-2-(2-[1,2,4]triazol-1-yl-ethylamino)-4H-thiazol-5-ylidenemethyl]-phenoxy}-3-trifluoromethyl-benzonitrile

734-{2-Methoxy-4-[2-(3-morpholin-4-yl-3-oxo-propylamino)-4-oxo-4H-thiazol-5-ylidenemethyl]-phenoxy}-3-trifluoromethyl-benzonitrile

74(2-{5-[4-(4-Cyano-2-trifluoromethyl-phenoxy)-3-methoxy-benzylidene]-4-oxo-4,5-dihydro-thiazol-2-ylamino}-ethyl)-urea

754-{2-Methoxy-4-[2-(methoxy-methyl-amino)-4-oxo-4H-thiazol-5-ylidenemethyl]-phenoxy}-3-trifluoromethyl-benzonitrile

76{5-[4-(4-Cyano-2-trifluoromethyl-phenoxy)-3-methoxy-benzylidene]-4-oxo-4,5-dihydro-thiazol-2-ylamino}-aceticacid

774-[2-Methoxy-4-(2-methylamino-4-oxo-4H-thiazol-5-ylidenemethyl)-phenoxy]-3-trifluoromethyl-benzonitrile

781-{5-[4-(4-Cyano-2-trifluoromethyl-phenoxy)-3-methoxy-benzylidene]-4-oxo-4,5-dihydro-thiazol-2-yl}-piperidine-4-carboxylicacid amide

791-{5-[4-(4-Cyano-2-trifluoromethyl-phenoxy)-3-methoxy-benzylidene]-4-oxo-4,5-dihydro-thiazol-2-yl}-piperidine-4-carboxylicacid methylester

804-(2-Methoxy-4-{2-[(morpholin-2-ylmethyl)-amino]-4-oxo-4H-thiazol-5-ylidenemethyl}-phenoxy)-3-trifluoromethyl-benzonitrile

814-[4-(2-Dimethylamino-4-oxo-4H-thiazol-5-ylidenemethyl)-2-methoxy-phenoxy]-3-trifluoromethyl-benzonitrile

824-{5-[4-(4-Cyano-2-trifluoromethyl-phenoxy)-3-methoxy-benzylidene]-4-oxo-4,5-dihydro-thiazol-2-ylamino}-butyricacid methyl ester

831-{5-[4-(4-Cyano-2-trifluoromethyl-phenoxy)-3-methoxy-benzylidene]-4-oxo-4,5-dihydro-thiazol-2-yl}-piperidin-4-yl)-aceticacid methyl ester

84{5-[4-(4-Cyano-2-trifluoromethyl-phenoxy)-3-methoxy-benzylidene]-4-oxo-4,5-dihydro-thiazol-2-ylamino}-aceticacid methyl ester

854-{4-[2-(3,5-Difluoro-benzylamino)-4-oxo-4H-thiazol-5-ylidenemethyl]-2-methoxy-phenoxy}-3-trifluoromethyl-benzonitrile

864-{4-[2-(4-Dimethylamino-piperidin-1-yl)-4-oxo-4H-thiazol-5-ylidenemethyl]-2-methoxy-phenoxy}-3-trifluoromethyl-benzonitrile

874-{4-[2-(2-Amino-ethylamino)-4-oxo-4H-thiazol-5-ylidenemethyl]-2-methoxy-phenoxy}-3-trifluoromethyl-benzonitrileHCl salt

884-(4-{2-[(Furan-3-ylmethyl)-amino]-4-oxo-4H-thiazol-5-ylidenemethyl}-2-methoxy-phenoxy)-3-trifluoromethyl-benzonitrile

894-(2-Methoxy-4-{4-oxo-2-[(thiophen-3-ylmethyl)-amino]-4H-thiazol-5-ylidenemethyl}-phenoxy)-3-trifluoromethyl-benzonitrile

904-{4-[2-(3-Fluoro-pyrrolidin-1-yl)-4-oxo-4H-thiazol-5-ylidenemethyl]-2-methoxy-phenoxy}-3-trifluoromethyl-benzonitrile

914-{4-[2-(2-Fluoro-ethylamino)-4-oxo-4H-thiazol-5-ylidenemethyl]-2-methoxy-phenoxy}-3-trifluoromethyl-benzonitrile

924-{4-[2-(2,2-Difluoro-ethylamino)-4-oxo-4H-thiazol-5-ylidenemethyl]-2-methoxy-phenoxy}-3-trifluoromethyl-benzonitrile

934-{4-[2-(3-Fluoro-pyrrolidin-1-yl)-4-oxo-4H-thiazol-5-ylidenemethyl]-2-methoxy-phenoxy}-3-trifluoromethyl-benzonitrile

944-{2-Methoxy-4-[2-(4-methyl-3-oxo-piperazin-1-yl)-4-oxo-4H-thiazol-5-ylidenemethyl]-phenoxy}-3-trifluoromethyl-benzonitrile

954-{4-[2-(3-Amino-2-hydroxy-propylamino)-4-oxo-4H-thiazol-5-ylidenemethyl]-2-methoxy-phenoxy}-3-trifluoromethyl-benzonitrile

964-{2-Fluoro-4-[2-(2-fluoro-ethylamino)-4-oxo-4H-thiazol-5-ylidenemethyl]-phenoxy}-3-trifluoromethyl-benzonitrile

974-{4-[2-(2,2-Difluoro-ethylamino)-4-oxo-4H-thiazol-5-ylidenemethyl]-2-fluoro-phenoxy}-3-trifluoromethyl-benzonitrile

984-{2-Fluoro-4-[4-oxo-2-(2-[1,2,4]triazol-1-yl-ethylamino)-4H-thiazol-5-ylidenemethyl]-phenoxy}-3-trifluoromethyl-benzonitrile

994-(2-Fluoro-4-{4-oxo-2-[2-(3-oxo-piperazin-1-yl)-ethylamino]-4H-thiazol-5-ylidenemethyl}-phenoxy)-3-trifluoromethyl-benzonitrile

1004-(2-Fluoro-4-{4-oxo-2-[3-(3-oxo-piperazin-1-yl)-propylamino]-4H-thiazol-5-ylidenemethyl}-phenoxy)-3-trifluoromethyl-benzonitrile

1014-(2-Methoxy-4-{4-oxo-2-[3-(3-oxo-piperazin-1-yl)-propylamino]-4H-thiazol-5-ylidenemethyl}-phenoxy)-3-trifluoromethyl-benzonitrile

1024-{4-[2-(3-Hydroxy-piperidin-1-yl)-4-oxo-4H-thiazol-5-ylidenemethyl]-2-methoxy-phenoxy}-3-trifluroomethyl-benzonitrile

1034-{2-Fluoro-4-[2-(3-hydroxy-piperidin-1-yl)-4-oxo-4H-thiazol-5-ylidenemethyl]-phenoxy}-3-trifluoromethyl-benzonitrile

1044-(2-Fluoro-4-{2-[2-(4-methyl-piperazin-1-yl)-ethylamino]-4-oxo-4H-thiazol-5-ylidenemethyl}-phenoxy)-3-trifluoromethyl-benzonitrile

1054-(2-Methoxy-4-{4-oxo-2-[2-(3-oxo-piperazin-1-yl)-ethylamino]-4H-thiazol-5-ylidenemethyl}-phenoxy)-3-trifluoromethyl-benzonitrile

1061-{5-[4-(4-Cyano-2-trifluoromethyl-phenoxy)-3-methoxy-benzylidene]-4-oxo-4,5-dihydro-thiazol-2-yl}-azetidine-3-carboxylicacid

1074-(2-Methoxy-4-{4-oxo-2-[(1H-tetrazol-5-ylmethyl)-amino]-4H-thiazol-5-ylidenemethyl}-phenoxy)-3-trifluoromethyl-benzonitrile

1084-(2-Fluoro-4-{4-oxo-2-[(1H-tetrazol-5-ylmethyl)-amino]-4H-thiazol-5-ylidenemethyl}-phenoxy)-3-trifluoromethyl-benzonitrile

1094-(2-Methoxy-4-{4-oxo-2-[2-(tetrahydro-pyran-4-yl)-ethylamino]-4H-thiazol-5-ylidenemethyl}-phenoxy)-3-trifluoromethyl-benzonitrile

1104-(2-Fluoro-4-{4-oxo-2-[2-(tetrahydro-pyran-4-yl)-ethylamino]-4H-thiazol-5-ylidenemethyl}-phenoxy)-3-trifluoromethyl-benzonitrile

1114-(4-{2-[1-(2-Hydroxy-ethyl)-piperidin-4-ylamino]-4-oxo-4H-thiazol-5-ylidenemethyl}-2-methoxy-phenoxy)-3-trifluroomethyl-benzonitrile

1124-(2-Fluoro-4-{2-[1-(2-hydroxy-ethyl)-piperidin-4-ylamino]-4-oxo-4H-thiazol-5-ylidenemethyl}-phenoxy)-3-trifluoromethyl-benzonitrile

1131-{5-[3-Methoxy-4-(4-methoxycarbonyl-2-trifluoromethyl-phenoxy)-benzylidene]-4-oxo-4,5-dihydro-thiazol-2-yl}-piperidine-4-carboxylicacid methyl ester

1144-{4-[2-(3-Hydroxy-piperidin-1-yl)-4-oxo-4H-thiazol-5-ylidenemethyl]-2-methoxy-phenoxy}-3-trifluoromethyl-benzamide

1154-{2-Methoxy-4-[4-oxo-2-(3-oxo-piperazin-1-yl)-4H-thiazol-5-ylidenemethyl]-phenoxy}-3-trifluoromethyl-benzamide

1161-{5-[4-(4-Cyano-2-trifluoromethyl-phenoxy)-3-fluoro-benzylidene]-4-oxo-4,5-dihydro-thiazol-2-yl}-azetidine-3-carboxylicacid

1172-[Bis-(2-hydroxy-ethyl)-amino]-5-[4-(2,4-bis-trifluoromethyl-phenoxy)-3-methoxy-benzylidene]-thiazol-4-one

1181-{5-[4-(2-Isopropyl-phenoxy)-benzylidene]-4-oxo-4,5-dihydro-thiazol-2-yl}-azetidine-3-carboxylicacid

1191-{5-[3-Methoxy-4-(2-trifluoromethyl-phenoxy)-benzylidene]-4-oxo-4,5-dihydro-thiazol-2-yl}-azetidine-3-carboxylicacid

C) Synthesis

The invention provides methods of making the disclosed compoundsaccording to traditional organic synthetic methods as well as matrix orcombinatorial synthetic methods. Schemes 1-4 describe suggestedsynthetic routes. Using the scheme, the guidelines below, and theexamples, a person of skill in the art may develop analogous or similarmethods for a given compound that is within the invention. These methodsare representative of the synthetic schemes, but are not to be construedas limiting the scope of the invention.

Where the compounds according to this invention have at least one chiralcenter, they may accordingly exist as enantiomers. Where the compoundspossess two or more chiral centers, they may additionally exist asdiastereomers. Where the processes for the preparation of the compoundsaccording to the invention give rise to mixtures of stereoisomers, theseisomers may be separated by conventional techniques such as preparativechromatography. The compounds may be prepared in racemic form or asindividual enantiomers or diasteromers by either stereospecificsynthesis or by resolution. The compounds may, for example, be resolvedinto their component enantiomers or diastereomers by standardtechniques, such as the formation of stereoisomeric pairs by saltformation with an optically active base, followed by fractionalcrystallization and regeneration of the free acid. The compounds mayalso be resolved by formation of stereoisomeric esters or amides,followed by chromatographic separation and removal of the chiralauxiliary. Alternatively, the compounds may be resolved using a chiralHPLC column. It is to be understood that all stereoisomers, racemicmixtures, diastereomers, geometric isomers, and enantiomers thereof areencompassed within the scope of the present invention.

Furthermore, some of the crystalline forms for the compounds may existas polymorphs and as such are intended to be included in the presentinvention. In addition, some of the compounds may form solvates withwater (i.e., hydrates) or common organic solvents, and such solvates arealso intended to be encompassed within the scope of this invention.

Examples of the described synthetic routes include Schemes 1-4, Examples1 through 119, and General Procedures A-C. Compounds analogous to thetarget compounds of these examples can be made according to similarroutes. The disclosed compounds are useful as pharmaceutical agents asdescribed herein.

Abbreviations or acronyms useful herein include:

-   -   AIBN (2,2′-Azobisisobutyronitrile)    -   Boc (tert butyl carbamate)    -   BOP (Benzotriazol-1-yloxy)tris(dimethylamino)phosphonium        hexfluorophosphate)    -   BuLi (butyllithium)    -   DIBAL-H (Diisobutylaluminum hydride)    -   DCM (Dichloromethane)    -   DIEA (Diisopropylethylamine)    -   DMAP (4-(dimethylamino)pyridine)    -   DME (Ethylene glycol dimethyl ether)    -   DMF (dimethylformamide)    -   DMPU (1,3-Dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone)    -   DMSO (methyl sulfoxide)    -   EDC (N-(3-Dimethylaminopropyl)-N′-ethylcarbodiimide)    -   EDCl (1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide        hydrochloride)    -   Et (ethyl)    -   EtOAc (ethyl acetate)    -   h or hr (hour(s))    -   HATU (O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium        hexafluorophosphate)    -   HMPA (Hexamethylphosphoramide)    -   HOBt (1-Hydroxybenzotriazole monohydrate)    -   LCMS (high pressure liquid chroatography with mass spectrometer)    -   LDA (Lithium diisopropylamide)    -   LHMDS (lithium hexamethyl disilazide)    -   Me (methyl)    -   MeOH (methyl alcohol)    -   Mg (milligram)    -   MOM (Methoxymethyl)    -   NaHMDS (sodium hexamethyl disilazide)    -   NaO^(t)Bu (sodium tert-butoxide)    -   NBS (N-Bromosuccinimide)    -   NMP (N-Methyl Pyrrolidinone)    -   N,N-DMA (N,N-dimethylacetamide)    -   rt or RT (room temperature)    -   SPE (solid phase extraction)    -   TBTU (O-Benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium        hexafluorophosphate)    -   TEMPO (2,2,6,6-tetramethyl-1-piperdinyloxy, free radical)    -   TFA (trifluoroacetic acid);    -   THF (tetrahydrofuran)    -   TLC (thin layer chromatography)

General Guidance

The compounds of Formula (I), wherein X, R₁, R₂, R₃, R₄, R₅ and R₆ aredefined as in Formula I, may be synthesized as outlined by the generalsynthetic route illustrated in Scheme 1. Treatment of an appropriatehydoxybenzaldehyde II and aryl fluoride III, both of which are eithercommercially available or can be made from commercially availablestarting materials, with a base such as K₂CO₃, Cs₂CO₃, NaH, and thelike, in a solvent such as NMP, DMF, THF, and the like, at a temperaturepreferably between 25-150° C. can provide the phenoxyaldehyde IV.Knoevenagel reaction of aldehyde IV with a suitably compound of formulaV in the presence of a catalytic amount of base such as piperidine andan acid such as benzoic acid can provide compound VI. The Knoevenagelreaction is typically performed in an aprotic solvent such as toluene ata temperature preferably between 100-200° C. The reaction betweenaldehyde IV and rhodanine V may also be performed with a base such assodium acetate in a solvent such as acetonitrile at a temperaturepreferably between 50-150° C., or in the presence of ammonium acetate inacetic acid at a temperature preferably between 50-150° C. The compoundof formula VI is reacted with a compound of formula R₇Y, wherein R₇ is asuitably selected alkyl such as methyl, ethyl, isopropyl, and the like,and Y, a suitably selected leaving group such as Cl, Br, I, tosylate,mesylate, and the like, a known compound or compound prepared by knownmethods, in the presence of a base such as K₂CO₃, Et₃N, DIEA, and thelike, in an organic solvent such as MeOH, DCM, THF, and the like, at atemperature preferably between 25-80° C., to yield the correspondingcompound of formula VII.

Treatment of VII with an appropriate amine R₅R₆NH in a solvent such asacetonitrile, MeOH, DMF, and the like, at a temperature preferablybetween 25-180° C. can provide compounds of Formula (I).

Compound of formula (I) wherein X, R₁, R₂, R₃, R₄, R₅ and R₆ are definedas in Formula I, may be prepared according to the process outlined inScheme 2. Treatment of an appropriate benzaldehyde VIII, wherein Z is asuitable leaving group such as F, Br, I, triflate, and the like, with asuitable phenol IX, both of which are either commercially available orcan be made from commercially available starting materials, with a basesuch as K₂CO₃, Cs₂CO₃, NaH, and the like, in a solvent such as NMP, DMF,THF, and the like, at a temperature preferably between 25-180° C. canprovide the phenoxyaldehyde IV. Knoevenagel reaction of aldehyde IV witha suitable compound of formula V in the presence of a catalytic amountof base such as piperidine and an acid such as benzoic acid can providecompound VI. The Knoevenagel reaction is typically performed in anaprotic solvent such as toluene at a temperature preferably between100-200° C. The reaction between aldehyde IV and a suitable compound offormula V may also be performed with a base such as sodium acetate in asolvent such as acetonitrile at a temperature preferably between 50-150°C., or in the presence of ammonium acetate in acetic acid at atemperature preferably between 50-150° C. The compound of formula VI isreacted with a compound of formula R₇Y, wherein R₇ is a suitablyselected alkyl such as methyl, ethyl, isopropyl, and the like, and Y, asuitably selected leaving group such as Cl, Br, I, tosylate, mesylate,and the like, a known compound or compound prepared by known methods, inthe presence of a base such as K₂CO₃, Et₃N, DIEA, and the like, in anorganic solvent such as MeOH, DCM, THF, and the like, at a temperaturepreferably between 25-80° C., to yield the corresponding compound offormula VII. Treatment of VII with an appropriate amine R₅R₆NH in asolvent such as acetonitrile, MeOH, DMF, and the like, at a temperaturepreferably between 25-150° C. can provide compounds of Formula (I).

The compounds of Formula (I), wherein X is S, and R₁, R₂, R₃, R₄, R₅ andR₆ are defined as in Formula I, may alternatively be synthesized asoutlined by the general synthetic route illustrated in Scheme 3.Accordingly, a suitable compound of formula V, a known compound orcompound prepared by known methods, is reacted with a compound offormula R₇Y, wherein R₇ is a suitably selected alkyl such as methyl,ethyl, isopropyl, and the like, and Y, a suitably selected leaving groupsuch as Cl, Br, I, tosylate, mesylate, and the like, a known compound orcompound prepared by known methods, in the presence of a base such asK₂CO₃, Et₃N, DIPEA, and the like, in an organic solvent such as MeOH,DCM, THF, and the like, at a temperature preferably between 25-80° C.,to yield the corresponding compound of formula X. Treatment of X with anappropriate amine R₅R₆NH in a solvent such as acetonitrile, MeOH, DMF,and the like, at a temperature preferably between 25-150° C. can providecompounds of Formula Xi. Treatment of an appropriate hydoxybenzaldehydeII and aryl fluoride III, both of which are either commerciallyavailable or can be made from commercially available starting materials,with a base such as K₂CO₃, Cs₂CO₃, NaH, and the like, in a solvent suchas NMP, DMF, THF, and the like, at a temperature preferably between25-180° C. can provide the phenoxyaldehyde IV.

Knoevenagel reaction of aldehyde IV with a suitably compound of formulaXI in the presence of a catalytic amount of base such as piperidine andan acid such as benzoic acid can provide compounds of Formula (I). TheKnoevenagel reaction is typically performed in an aprotic solvent suchas toluene at a temperature preferably between 100-200° C. The reactionbetween aldehyde IV and a suitably compound of formula XI may also beperformed with a base such as sodium acetate in a solvent such asacetonitrile at a temperature preferably between 50-150° C., or in thepresence of ammonium acetate in acetic acid at a temperature preferablybetween 50-150° C.

Compounds of formula (I) wherein X, R₁, R₂, R₃, R₄, R₅ and R₆ aredefined as in Formula I, may be alternatively prepared according to theprocess outlined in Scheme 4. Treatment of an appropriate benzaldehydeVIII, wherein Z is a suitable leaving group such as F, Br, I, triflate,and the like, with a suitable phenol IX, both of which are eithercommercially available or can be made from commercially availablestarting materials, with a base such as K₂CO₃, Cs₂CO₃, NaH, and thelike, in a solvent such as NMP, DMF, THF, and the like, at a temperaturepreferably between 25-180° C. can provide the phenoxyaldehyde IV.Knoevenagel reaction of aldehyde IV with a suitably compound of formulaXI in the presence of a catalytic amount of base such as piperidine andan acid such as benzoic acid can provide compounds of Formula (I). TheKnoevenagel reaction is typically performed in an aprotic solvent suchas toluene at a temperature preferably between 100-200° C. The reactionbetween aldehyde IV and a suitably compound of formula XI may also beperformed with a base such as sodium acetate in a solvent such asacetonitrile at a temperature preferably between 50-150° C., or in thepresence of ammonium acetate in acetic acid at a temperature preferablybetween 50-150° C.

EXAMPLES

General Procedure A: A solution of an appropriate substitutedbenzaldehyde (1.65 g, 10.86 mmol) and aryl fluoride (10.26 mmol) in DMF(15 mL) was treated with K₂CO₃ (2.83 g, 21.72 mmol), and the mixture washeated in an oil bath at 80° C. for 12 h. The reaction was cooled to RTand partitioned between EtOAc and H₂O. The organic phase was washed withwater (3×), dried over Na₂SO₄ and concentrated in vacuo. Silica gelchromtagraphy (EtOAc/hexanes) afforded the pure product.

General Procedure B: 2-Amino-thiazol-4-one (2.55 g, 21.79 mmol) andaldehyde from Procedure A (21.79 mmol) were dissolved in toluene (150mL) and treated with benzoic acid (3.27 mmol) and piperidine (2.83mmol). The flask was equipped with a Dean-Stark trap, and the reactionwas refluxed in a 130° C. oil bath for 12 h. After cooling to RT, theproduct was collected by filtration and triturated with hexanes toafford a pure product.

General Procedure C: To a mixture of 2-Amino-thiazol-4-one (117 mg, 1.0mmol) and aldehyde from Procedure A (1.0 mmol) was added acetic acid(1.0 mL) and NH₄OAc (2.0 mmol). The suspension was heated at 100° C.(aluminum heating block) for 2 h. The product was collected byfiltration, washed with water and triturated with EtOAc/hexanes toafford a pure product.

Example 14-[4-(2-Amino-4-oxo-4H-thiazol-5-ylidenemethyl)-2-methoxy-phenoxyl-3-trifluoromethyl-benzonitrile

A. 4-(4-Formyl-2-methoxy-phenoxy)-3-trifluoromethyl-benzonitrile wasprepared from vanillin and 4-fluoro-3-trifluoromethylbenzonitrilefollowing General Procedure A. ¹H NMR (400 Hz, CDCl₃) δ 10.00 (s, 1H),8.00 (m, 1H), 7.68 (dd, 1H), 7.58-7.53 (m, 2H), 7.29 (d, 1H), 6.75 (d,1H), 3.83 (s, 3H); LC/MS (m/z) [M+1]⁺322.1 (calculated for C₁₆H₁₁F₃NO₃,322.06).

B.4-[4-(2-Amino-4-oxo-4H-thiazol-5-ylidenemethyl)-2-methoxy-phenoxy]-3-trifluoromethyl-benzonitrilewas prepared using 2-amino-thiazol-4-one and4-(4-Formyl-2-methoxy-phenoxy)-3-trifluoromethyl-benzonitrile accordingto General Procedure B. ¹H NMR (400 Hz, DMSO-d6) δ 8.96 (bs, NH), 8.74(bs, NH), 8.32 (d, 1H), 7.99 (dd, 1H), 7.65 (d, 1H), 7.47 (d, 1H), 7.36(d, 1H), 7.24 (d, 1H), 6.89 (d, 1H), 3.88 (s, 3H); LC/MS (m/z)[M+1]⁺420.0 (C₁₉H₁₃F₃N₃O₃S, 420.38).

Example 24-[4-(2-Amino-4-oxo-4H-thiazol-5-ylidenemethyl)-2-methoxy-phenoxy]-3-chloro-benzonitrile

A. 4-(2-Chloro-4-cyanophenoxy)-3-methoxybenzaldehyde was prepared fromvanillin and 3-Chloro-4-fluorobenzonitrile following General ProcedureA. ¹H NMR (400 Hz, CDCl₃) δ 9.95 (s, 1H), 7.76 (d, 1H), 7.56 (br s, 1H),7.50 (d, 1H), 7.45 (brd, 1H), 7.15 (d, 1H), 6.78 (d, 1H), 3.90 (s, 3H).

B.4-[4-(2-Amino-4-oxo-4H-thiazol-5-ylidenemethyl)-2-methoxy-phenoxy]-3-chloro-benzonitrilewas prepared using 2-amino-thiazol-4-one and4-(2-Chloro-4-cyanophenoxy)-3-methoxybenzaldehyde according to GeneralProcedure B. ¹H NMR (400 Hz, DMSO-d6) δ 9.47 (bs, NH), 9.21 (bs, NH),8.17 (d, 1H), 7.70 (dd, 1H), 7.64 (s, 1H), 7.46 (d, 1H), 7.32 (d, 1H),7.23 (dd, 1H), 6.81 (d, 1H), 3.79 (s, 3H); LC/MS (m/z) [M+1]⁺386.0(calculated for C₁₈H₁₃ClN₃O₃S, 386.82).

Example 34-[2-Chloro-4-(2-imino-4-oxo-thiazolidin-5-ylidenemethyl)-phenoxy]-3-trifluoromethyl-benzonitrile

A.4-[2-Chloro-4-(2,4-dioxo-thiazolidin-5-ylidenemethyl)-phenoxy]-3-trifluoromethylbenzonitrilewas prepared from 3-Chloro-4-hydroxybenzaldehyde and4-fluoro-3-trifluoromethylbenzonitrile following General Procedure A. ¹HNMR (400 MHz, CDCl₃) δ 9.99 (s, 1H), 8.06 (d, J=1.96 Hz), 8.02 (d,J=1.96 Hz, 1H), 7.87 (dd, J=8.22 and 1.96 Hz, 1H), 7.76 (dd, J=8.61 and1.96 Hz, 1H), 7.27 (d, J=8.61 Hz, 1H), 6.82 (d, J=8.61 Hz, 1H).

B.4-[2-Chloro-4-(2-imino-4-oxo-thiazolidin-5-ylidenemethyl)-phenoxy]-3-trifluoromethyl-benzonitrilewas prepared using 2-amino-thiazol-4-one and4-[2-Chloro-4-(2,4-dioxo-thiazolidin-5-ylidenemethyl)-phenoxy]-3-trifluoromethylbenzonitrileaccording to General Procedure C. ¹H NMR (400 MHz, DMSO-d6) δ 9.56 (br,1H), 9.24 (br, 1H), 8.40 (d, J=1.56 Hz, 1H), 8.08 (dd, J=8.6 and 1.95Hz, 1H), 7.90 (d, J=1.96 Hz, 1H), 7.65 (d, J=2.35 Hz, 1H), 7.63 (s, 1H),7.50 (d, J=8.61 Hz, 1H), 7.07 (d, J=8.61 Hz, 1H). LC/MS (m/z)[M+1]⁺424.2 (calculated for C₁₈H₁₀ClF₃N₃O₂S 424.0).

Example 44-[2-Fluoro-4-(2-imino-4-oxo-thiazolidin-5-ylidenemethyl)-phenoxyl-naphthalene-1-carbonitrile

A. 4-(2-Fluoro-4-formyl-phenoxy)-naphthalene-1-carbonitrile was preparedfrom 3-Fluoro-4-hydroxybenzaldehyde and4-Fluoro-naphthalene-1-carbonitrile following General Procedure A. ¹HNMR (400 MHz, CDCl₃) δ 9.99 (d, J=1.95 Hz, 1H), 8.38 (d, J=8.6 Hz, 1H),8.27 (d, J=8.6 Hz, 1H), 7.77-7.84 (3H), 7.69-7.74 (2H), 7.29 (d, J=7.43Hz, 1H), 6.83 (d, J=7.83 Hz, 1H).

B.4-[2-Fluoro-4-(2-imino-4-oxo-thiazolidin-5-ylidenemethyl)-phenoxy]-naphthalene-1-carbonitrilewas prepared using 2-amino-thiazol-4-one and4-(2-Fluoro-4-formyl-phenoxy)-naphthalene-1-carbonitrile followingGeneral Procedure C. ¹H NMR (400 MHz, DMSO-d6) δ 9.54 (br, 1H), 9.25(br, 1H), 8.42 (d, J=8.21 Hz, 1H), 8.15 (d, J=8.21 Hz, 1H), 8.08 (d,J=7.82 Hz, 1H), 7.91 (m, 1H), 7.81 (m, 1H), 7.7 (dd, J=12.13 and 2.34Hz, 1H), 7.64 (s, 1H), 7.49-7.57 (2H), 6.93 (d, J=7.83 Hz, 1H). LC/MS(m/z) [M+1]⁺390.2 (calculated for C₂₁H₁₃FN₃O₂S 390.1).

Example 54-[2-Methoxy-4-(2-morpholin-4-yl-4-oxo-4H-thiazol-5-ylidenemethyl)-phenoxy]-3-trifluoromethyl-benzonitrile

A.4-[2-Methoxy-4-(4-oxo-2-thioxo-thiazolidin-5-ylidenemethyl)-phenoxy]-3-trifluoromethyl-benzonitrile

The title compound was prepared using rhodanine and4-(4-Formyl-2-methoxy-phenoxy)-3-trifluoromethyl-benzonitrile accordingto General Procedure B. ¹H NMR (400 Hz, CDCl₃) δ 9.31 (bs, NH), 7.98(bs, 1H), 7.68 (dd, 1H), 7.64 (s, 1H), 7.18 (m, 3H), 6.77 (d, 1H), 3.83(s, 3H).

B.4-[2-Methoxy-4-(2-methylsulfanyl-4-oxo-4H-thiazol-5-ylidenemethyl)-phenoxy]-3-trifluoromethyl-benzonitrile

To a solution of4-[2-Methoxy-4-(4-oxo-2-thioxo-thiazolidin-5-ylidenemethyl)-phenoxy]-3-trifluoromethyl-benzonitrile(500 mg, 1.15 mmol) in DMF (5 mL) was added CH₃I (15 mL) and thesolution was heated to 40° C. in an aluminum heating block for 8 h. Thesolvent was concentrated in vacuo to afford the product. ¹H NMR (400 Hz,CDCl₃) δ 7.97 (bs, 1H), 7.68 (dd, 1H), 7.63 (s, 1H), 7.17 (m, 3H), 6.77(d, 1H), 3.08 (s, 3H), 2.95 (s, 3H).

C.4-[2-Methoxy-4-(2-morpholin-4-yl-4-oxo-4H-thiazol-5-ylidenemethyl)-phenoxy]-3-trifluoromethyl-benzonitrile

A solution of4-[2-Methoxy-4-(2-methylsulfanyl-4-oxo-4H-thiazol-5-ylidenemethyl)-phenoxy]-3-trifluoromethyl-benzonitrile(88 mg, 0.2 mmol) in CH₃CN (1 mL) was treated with morpholine (0.4 mmol)and heated to 60° C. in an aluminum heating block for 10 h. The solventwas removed in vacuo and the crude reaction mixture was purified bysilica gel chromatography (EtOAc/CH₂Cl₂) to afford the title compound.¹H NMR (400 Hz, CDCl₃) δ 7.95 (d, 1H), 7.79 (s, 1H), 7.66 (dd, 1H), 7.19(m, 3H), 6.76 (d, 1H), 4.10 (m, 2H), 3.84 (m, 4H), 3.78 (s, 3H), 3.64(m, 2H); LC/MS (m/z) [M+1]⁺490.3 (calculated for C₂₃H₁₉F₃N3O₄S, 490.47).

Example 64-[2-Fluoro-4-(2-morpholin-4-yl-4-oxo-4H-thiazol-5-ylidenemethyl)-phenoxy]-3-trifluoromethyl-benzonitrile

A.4-[2-Fluoro-4-(4-oxo-2-thioxo-thiazolidin-5-ylidenemethyl)-phenoxy]-3-trifluoromethyl-benzonitrilewas prepared using rhodanine and4-(2-Fluoro-4-formyl-phenoxy)-3-trifluoromethyl-benzonitrile accordingthe General Procedure B. ¹H NMR (400 Hz, DMSO-d₆) δ 8.41 (d, 1H), 8.11(dd, 1H), 7.76 (d, 1H), 7.67 (s, 1H), 7.51 (m, 2H), 7.23 (d, 1H).

B.4-[2-Fluoro-4-(2-methylsulfanyl-4-oxo-4H-thiazol-5-ylidenemethyl)-phenoxy]-3-trifluoromethyl-benzonitrilewas prepared using4-[2-Fluoro-4-(4-oxo-2-thioxo-thiazolidin-5-ylidenemethyl)-phenoxy]-3-trifluoromethyl-benzonitrileas described in Example 5B. ¹H NMR (400 Hz, DMSO-d₆) δ 8.01 (bs, 1H),7.80 (s, 1H), 7.75 (dd, 1H), 7.40 (m, 2H), 7.30 (d, 1H), 6.91 (d, 1H),2.85 (s, 3H).

C.4-[2-Fluoro-4-(2-morpholin-4-yl-4-oxo-4H-thiazol-5-ylidenemethyl)-phenoxy]-3-trifluoromethyl-benzonitrilewas prepared using4-[2-Fluoro-4-(2-methylsulfanyl-4-oxo-4H-thiazol-5-ylidenemethyl)-phenoxy]-3-trifluoromethyl-benzonitrileand morpholine as described in Example 5C. ¹H NMR (400 Hz, DMSO-d₆) δ8.40 (bs, 1H), 8.10 (d, 1H), 7.74 (d, 1H), 7.69 (s, 1H), 7.55 (m, 2H),7.18 (d, 1H), 3.92 (bs, 2H), 3.71 (m, 6H); LC/MS (m/z) [M+1]⁺478.2(calculated for C₂₂H₁₆F₄N₃O₃S, 478.43).

Example 7 4-{2-Methoxy-4-[2-(4-methyl-piperazin-1-yl)-4-oxo-4H-thiazol-5-ylidenemethyl]-phenoxy-3-trifluoromethyl-benzonitrile

Prepared as described in Example 5c except that N-methylpiperazine wasused in place of morpholine. ¹H NMR (400 MHz, CDCl₃) δ 7.90 (d, 1H),7.72 (s, 1H), 7.60 (dd, 1H), 7.13 (m, 2H), 7.09 (bs, 1H), 6.70 (d, 1H),4.08 (bs, 2H), 3.74 (s, 3H), 3.63 (bs, 2H), 2.55 (bs, 2H), 2.34 (s, 2H);LC/MS (m/z) [M+1]⁺503.4 (calculated for C₂₄H₂₂F₃N₄O₃S, 503.51).

Example 84-{2-Fluoro-4-[2-(4-methyl-piperazin-1-yl)-4-oxo-4H-thiazol-5-ylidenemethyl]-phenoxy-3-trifluoromethyl-benzonitrile

Prepared as described in Example 6c except that N-methylpiperazine wasused in place of morpholine. ¹H NMR (400 MHz, CDCl₃) δ 7.93 (d, 1H),7.68 (dd, 1H), 7.67 (s, 1H), 7.33 (m, 2H), 7.20 (m, 1H), 6.84 (d, 1H),4.04 (m, 1 H), 3.60 (m, 1H), 3.00 (m, 1H), 2.50 (m, 3H), 2.30 (s, 3H),2.22 (m, 1H), 1.55 (m, 1H); LC/MS (m/z) [M+1]⁺491.2 (calculated forC₂₃H₁₉F₄N₄O₂S, 491.47).

Example 94-[4-(2-Cyclopropylamino-4-oxo-4H-thiazol-5-ylidenemethyl)-2-methoxy-phenoxy]-3-trifluoromethyl-benzonitrile

Prepared as described in Example 5c except that cyclopropylamine wasused in place of morpholine. ¹ H NMR (400 MHz, CDCl₃) δ 7.97 (d, 1H),7.77 (s, 1H), 7.67 (dd, 1H), 7.28-7.19 (m, 3H), 6.79 (d, 1H), 3.83 (s,3H), 2.83 (m, 1H), 1.06-0.98 (m, 4H); LC/MS (m/z) [M+1]⁺460.1(calculated for C₂₂H₁₇F₃N₃O₃S, 460.09).

Example 104-[4-(2-Cyclopropylamino-4-oxo-4H-thiazol-5-ylidenemethyl)-2-fluoro-phenoxy]-3-trifluoromethyl-benzonitrile

Prepared as described in Example 6c except that cyclopropylamine wasused in place of morpholine. ¹H NMR (400 MHz, CDCl₃) δ 8.01 (d, 1H),7.76-7.72 (m, 2H), 7.48-7.42 (m, 2H), 7.32-7.27 (m, 1H), 6.92 (d, 1H),2.84 (m, 1H), 1.10-1.00 (m, 4H); LC/MS (m/z) [M+1]⁺448.1 (calculated forC₂₁H₁₄F₄N₃O₂S, 448.07).

Unless specified otherwise, Examples 11 to 117 were prepared accordinglyas described in Example 5C using the appropriatealkylsulfanyl-thiazol-one intermediate and amine (HNR₅R₆) to generatethe desired products.

Example 114-(4-{2-[(2-Dimethylamino-ethyl)-methyl-amino]-4-oxo-4H-thiazol-5-ylidenemethyl}-2-methoxy-phenoxy)-3-trifluoromethyl-benzonitrile

¹H NMR (400 Hz, DMSO) δ 8.34 (d, 1H), 8.02 (dd, 1H), 7.70 (d, 1H), 7.54(dd, 1H), 7.38 (dd, 1H), 7.32 (m, 1H), 6.90 (dd, 1H), 3.85 (t,1H), 3.80(d, 3H), 3.64 (t, 1H), 2.54 (m, 5H), 2.20 (d, 6H); LC/MS (m/z)[M+1]⁺505.0 (calculated for C₂₄H₂₃F₃N₄O₃S, 504.53).

Example 124-(4-{2-[Bis-(2-hydroxy-ethyl)-amino]-4-oxo-4H-thiazol-5-ylidenemethyl}-2-methoxy-phenoxy)-3-trifluoromethyl-benzonitrile

¹H NMR (400 Hz, CDCl₃) δ 7.97 (d, 1H), 7.65 (m, 2H), 7.10 (m, 3H), 6.72(d, 1H), 4.10 (t, 2H), 4.00 (m, 4H), 3.76 (m, 5H); LC/MS (m/z)[M+1]⁺508.3 (calculated for C₂₃H₂₀F₃N₃O₅S, 507.48).

Example 134-{2-Methoxy-4-[4-oxo-2-(pyrrolidin-3-ylamino)-4H-thiazol-5-ylidenemethyl]-phenoxy}-3-trifluoromethyl-benzonitrile

¹H NMR (400 Hz, CDCl₃) δ 7.94 (d, 1H), 7.66 (m, 2H), 7.16 (m, 3H), 6.76(d, 1H), 3.80 (d, 3H), 3.20 (m, 2H), 2.94 (d, 2H), 2.30 (m, 1H), 2.02(m, 1H), 1.25 (m, 1H); LC/MS (m/z) [M+1]⁺489.3 (calculated forC₂₃H₁₉F₃N₄O₃S, 488.48).

Example 14 4-{2-Methoxy-4-[2-(1-methyl-piperidin-4-ylamino)-4-oxo-4H-thiazol-5-ylidenemethyl]-phenoxy}-3-trifluoromethyl-benzonitrile

¹H NMR (400 Hz, CDCl₃) δ 7.95 (dd, 1H), 7.75 (d, 1H), 7.66 (m, 1H), 7.20(s, 1H), 7.12 (m, 2H), 6.76 (t, 1H), 4.23 (m, 0.5H), 3.78 (d, 3H), 3.38(m, 0.5H), 2.95 (d, 1H), 2.88 (d, 1H), 2.30 (d, 3H), 2.14 (m, 4H), 1.98(m, 1H), 1.76 (m, 1H); LC/MS (m/z) [M+1]⁺517.4 (calculated forC₂₅H₂₃F₃N₄O₃S, 516.54).

Example 15 4-{2-Methoxy-4-[4-oxo-2-(tetrahydro-pyran-4-ylamino)-4H-thiazol-5-ylidenemethyl]-phenoxy}-3-trifluoromethyl-benzonitrile

¹H NMR (400 Hz, CDCl₃) δ 7.97 (dd, 1H), 7.80 (s, 1H), 7.67 (m, 1H), 7.23(s, 1H), 7.16 (m, 2H), 6.78 (m, 1H), 4.10 (dd, 2H), 3.82 (d, 3H), 3.58(m, 3H), 2.18 (m, 2H), 1.65 (m, 2H); LC/MS (m/z) [M+1]⁺504.3 (calculatedfor C₂₄H₂₀F₃N₃O₄S, 503.49).

Example 164-(4-{2-[4-(2-Hydroxy-ethyl)-piperazin-1-yl]-4-oxo-4H-thiazol-5-ylidenemethyl}-2-methoxy-phenoxy)-3-trifluoromethyl-benzonitrile

¹H NMR (400 Hz, CDCl₃) δ 7.96 (d, 1H), 7.78 (s, 1H), 7.68 (dd, 1H), 7.20(d, 2H), 7.16 (s, 1H), 6.78 (d, 1H), 4.12 (m, 2H), 3.82 (s, 3H), 3.70(m, 4H), 2.70 (m, 6H), LC/MS (m/z) [M+1]⁺533.2 (calculated forC₂₅H₂₃F₃N₄O₄S, 532.54).

Example 174-(2-Methoxy-4-{4-oxo-2-[(pyridin-2-ylmethyl)-amino]-4H-thiazol-5-ylidenemethyl}-phenoxy)-3-trifluoromethyl-benzonitrile

¹H NMR (400 Hz, CDCl₃) δ 8.58 (d, 1H), 8.44 (bs, 1H), 7.96 (d, 1H), 7.72(m, 3H), 7.38 (d, 1H), 7.32 (m, 1H), 7.14 (m, 3H), 6.80 (d, 1H), 5.02(s, 2H), 3.82 (d, 3H); LC/MS (m/z) [M+1]⁺511.2 (calculated forC₂₅H₁₇F₃N₄O₃S, 510.49).

Example 184-{2-Methoxy-4-[2-(2-methoxy-ethylamino)-4-oxo-4H-thiazol-5-ylidenemethyl]-phenoxy}-3-trifluoromethyl-benzonitrile

¹H NMR (400 Hz, CDCl₃) δ 7.97 (s, 1H), 7.80 (s, 1H), 7.67 (d, 1H), 7.18(m, 3H), 6.78 (d, 1H), 3.92 (m, 1H), 3.80 (d, 3H), 3.62 (t, 2H), 3.42(s, 3H), 3.36 (t, 2); LC/MS (m/z) [M+1]⁺478.1 (calculated forC₂₂H₁₈F₃N₃O₄S, 477.46).

Example 194-(2-Methoxy-4-{4-oxo-2-[(pyridin-3-ylmethyl)-amino]-4H-thiazol-5-ylidenemethyl}-phenoxy)-3-trifluoromethyl-benzonitrile

¹H NMR (400 Hz, CDCl₃) δ 8.60 (m, 2H), 7.97 (d, 1H), 7.80 (m, 2H), 7.68(m, 1H), 7.34 (m, 1H), 7.17 (m, 3H), 6.78 (d, 1H), 4.70 (s, 2H), 3.80(d, 3H); LC/MS (m/z) [M+1]⁺511.2 (calculated for C₂₅H₁₇F₃N₄O₃S, 510.49).

Example 20 4-{2-Methoxy-4-[4-oxo-2-(2-pyrrolid in-1-yl-ethylamino)-4H-thiazol-5-ylidenemethyl]-phenoxy}-3-trifluoromethyl-benzonitrile

¹H NMR (400 Hz, CDCl₃) δ 7.96 (d, 1H), 7.74 (m, 1H), 7.52 (s, 1H), 7.20(m, 1H), 7.05 (m, 2H), 6.89 (d, 1H), 3.80 (m, 5H), 2.86 (m, 2H), 2.70(m, 3H), 2.60 (m, 1H), 1.85 (m, 4H); LC/MS (m/z) [M+1]⁺517.2 (calculatedfor C₂₅H₂₃F₃N₄O₃S, 516.54).

Example 21 4-{2-Methoxy-4-[4-oxo-2-(3-oxo-piperazin-1-yl)-4H-thiazol-5-ylidenemethyl]-phenoxy}-3-trifluoromethyl-benzonitrile

¹H NMR (400 Hz, DMSO) δ 8.40 (bs, 1H), 8.34 (d, 1H), 8.02 (dd, 1H), 7.75(d, 1H), 7.54 (dd, 1H), 7.36 (m, 2H), 6.92 (dd, 1H), 4.38 (s, 1H), 4.24(s, 1H), 4.07 (t, 1H), 3.86 (t, 1H), 3.80 (d, 3H), 3.40 (m, 2H); LC/MS(m/z) [M+1]⁺503.2 (calculated for C₂₃H₁₇F₃N₄O₄S, 502.47).

Example 22

4-(2-Methoxy-4-{4-oxo-2-[3-(2-oxo-pyrrolidin-1-yl)-propylamino]-4H-thiazol-5-ylidenemethyl}-phenoxy)-3-trifluoromethyl-benzonitrile

¹H NMR (400 Hz, CDCl₃) δ 8.20 (bs, 1H), 7.96 (d, 1H), 7.76 (s, 1H), 7.66(dd, 1H), 7.18 (m, 2H), 7.14 (d, 1H), 6.77 (d, 1H), 3.80 (s, 3H), 3.67(m, 2H), 3.45 (m, 4H), 2.50 (t, 2H), 2.14 (m, 2H), 1.86 (m, 2H); LC/MS(m/z) [M+1]⁺545.2 (calculated for C₂₆H₂₃F₃N₄O₄S, 544.55).

Example 23 4-(4-{2-[(2,3-Dihydroxy-propyl)-methyl-amino]-4-oxo-4H-thiazol-5-ylidenemethyl}-2-methoxy-phenoxy)-3-trifluoromethyl-benzonitrile

¹H NMR (400 Hz, CDCl₃) δ7.97 (d, 1H), 7.76 (s, 1H), 7.67 (dd, 1H), 7.20(d, 2H), 7.15 (d, 1H), 6.77 (d, 1H), 4.13 (bs, 1H), 3.98 (m, 1H), 3.89(m, 1H), 3.81 (s, 3H), 3.66 (m, 3H), 3.40 (s, 3H); LC/MS (m/z)[M+1]⁺508.1 (calculated for C₂₃H₂₀F₃N₃O₅S, 507.48).

Example 244-(2-Methoxy-4-{4-oxo-2-[(pyridin-4-ylmethyl)-amino]-4H-thiazol-5-ylidenemethyl}-phenoxy)-3-trifluoromethyl-benzonitrile

¹H NMR (400 Hz, CDCl₃) δ 8.60 (m, 2H), 7.97 (d, 1H), 7.80 (d, 1H), 7.67(dd, 1H), 7.36 (d, 1H), 7.28 (d, 1H), 7.20 (m, 2H), 7.13 (s, 1H), 6.76(d, 1H), 4.90 (d, 1H), 4.65 (d, 1H), 3.80 (d, 3H); LC/MS (m/z)[M+1]⁺511.1 (calculated for C₂₅H₁₇F₃N₄O₃S, 510.49).

Example 254-{2-Methoxy-4-[4-oxo-2-(2-piperidin-1-yl-ethylamino)-4H-thiazol-5-ylidenemethyl]-phenoxy}-3-trifluoromethyl-benzonitrile

¹H NMR (400 Hz, CDCl₃) δ 7.96 (d, 1H), 7.76 (d, 1H), 7.67 (dd, 1H), 7.18(m, 2H), 7.12 (d, 1H), 6.78 (d, 1H), 3.80 (m, 5H), 2.62 (qt, 2H), 2.46(m, 4H), 1.60 (m, 4H), 1.50 (m, 2H); LC/MS (m/z) [M+1]⁺531.3 (calculatedfor C₂₆H₂₅F₃N₄O₃S, 530.56).

Example 264-{4-[2-(3-Dimethylamino-propylamino)-4-oxo-4H-thiazol-5-ylidenemethyl]-2-methoxy-phenoxy}-3-trifluoromethyl-benzonitrile

¹H NMR (400 Hz, CDCl₃) δ 7.96 (d, 1H), 7.76 (d, 1H), 7.66 (dd, 1H), 7.18(m, 3H), 6.76 (dd, 1H), 3.85 (t, 1H), 3.80 (d, 3H), 3.60 (t, 1H), 2.60(m, 2H), 2.32 (d, 6H), 1.85 (m, 2H); LC/MS (m/z) [M+1]⁺505.3 (calculatedfor C₂₄H₂₃F₃N₄O₃S, 504.53).

Example 274-{2-Methoxy-4-[2-(3-morpholin-4-yl-propylamino)-4-oxo-4H-thiazol-5-ylidenemethyl]-phenoxy}-3-trifluoromethyl-benzonitrile

¹H NMR (400 Hz, CDCl₃) δ7.95 (d, 1H), 7.74 (s, 1H), 7.66 (dd, 1H), 7.16(m, 3H), 6.76 (d, 1H), 3.80 (m, 9H), 2.68 (m, 6H), 2.00 (m, 2H); LC/MS(m/z) [M+1]⁺547.1 (calculated for C₂₆H₂₅F₃N₄O₄S, 546.56).

Example 28 4-{2-Methoxy-4-[4-oxo-2-(2-pyridin -4-yl-ethylamino)-4H-thiazol-5-ylidenemethyl]-phenoxy}-3-trifluoromethyl-benzonitrile

¹H NMR (400 Hz, CDCl₃) δ 8.54 (dd, 1H), 8.49 (dd, 1H), 7.97 (dd, 1H),7.80 (d, 1H), 7.67 (m, 1H), 7.18 (m, 5H), 6.77 (t, 1H), 4.04 (qt, 1H),3.80 (m, 4H), 3.20 (t, 1H), 3.05 (t, 1H); LC/MS (m/z) [M+1]⁺525.1(calculated for C₂₆H₁₉F₃N₄O₃S, 524.52).

Example 29 4-{2-Methoxy-4-[4-oxo-2-(2-pyridin -3-yl-ethylamino)-4H-thiazol-5-ylidenemethyl]-phenoxy}-3-trifluoromethyl-benzonitrile

¹H NMR (400 Hz, CDCl₃) δ 8.54 (d, 1H), 8.49 (dd, 1H), 7.97 (dd, 1H),7.78 (d, 1H), 7.67 (m, 1H), 7.18 (m, 5H), 6.77 (t, 1H), 4.04 (qt, 1H),3.80 (m, 4H), 3.24 (t, 1H), 3.10 (t, 1H); LC/MS (m/z) [M+1]⁺525.1(calculated for C₂₆H₁₉F₃N₄O₃S, 524.52).

Example 304-{2-Methoxy-4-[4-oxo-2-(2-pyrazol-1-yl-ethylamino)-4H-thiazol-5-ylidenemethyl]-phenoxy}-3-trifluoromethyl-benzonitrile

¹H NMR (400 Hz, CDCl₃) δ 7.97 (d, 1H), 7.82 (s, 1H), 7.70 (dd, 1H), 7.60(d, 1H), 7.50 (d, 1H), 7.20 (m, 4H), 6.78 (d, 1H), 4.45 (t, 1H), 4.20(t, 1H), 3.82 (s, 3H), 2.20 (t, 2H); LC/MS (m/z) [M+1]⁺514.2 (calculatedfor C₂₄H₁₈F₃N₅O₃S, 513.49).

Example 314-{4-[2-(4-Acetyl-piperazin-1-yl)-4-oxo-4H-thiazol-5-ylidenemethyl]-2-methoxy-phenoxy}-3-trifluoromethyl-benzonitrile

¹H NMR (400 Hz, CDCl₃) δ 7.97 (d, 1H), 7.82 (s, 1H), 7.67 (dd, 1H), 7.22(d, 2H), 7.17 (d, 1H), 6.78 (d, 1H), 4.12 (m, 2H), 3.82 (m, 5H), 3.65(m, 4H), 2.18 (m, 3H), LC/MS (m/z) [M+1]⁺531.2 (calculated forC₂₅H₂₁F₃N₄O₄S, 530.52).

Example 324-{4-[2-(2-Hydroxy-ethylamino)-4-oxo-4H-thiazol-5-ylidenemethyl]-2-methoxy-phenoxy}-3-trifluoromethyl-benzonitrile

¹H NMR (400 Hz, DMSO) δ 8.34 (d, 1H), 8.02 (dd, 1H), 7.66 (s, 1H), 7.50(d, 1H), 7.39 (d, 1H), 7.25 (dd, 1H), 6.92 (d, 1H), 3.82 (s, 3H), 3.62(m, 4H); LC/MS (m/z) [M+1]⁺464.1 (calculated for C₂₁H₁₆F₃N₃O₄S, 463.43).

Example 334-{2-Methoxy-4-[2-(2-morpholin-4-yl-ethylamino)-4-oxo-4H-thiazol-5-ylidenemethyl]-phenoxy}-3-trifluoromethyl-benzonitrile

¹H NMR (400 Hz, CDCl₃) δ 7.97 (d, 1H), 7.79 (s, 1H), 7.67 (dd, 1H), 7.17(m, 3H), 6.78 (d, 1H), 3.80 (m, 9H), 2.78 (t, 1H), 2.69 (t, 1H), 2.55(m, 4H); LC/MS (m/z) [M+1 ]⁺533.1 (calculated for C₂₅H₂₃F₃N₄O₄S,532.54).

Example 344-{4-[2-(2R,3-Dihydroxy-propylamino)-4-oxo-4H-thiazol-5-ylidenemethyl]-2-methoxy-phenoxy}-3-trifluoromethyl-benzonitrile

¹H NMR (400 Hz, DMSO) δ 8.34 (d, 1H), 8.02 (dd, 1H), 7.64 (s, 1H), 7.50(d, 1H), 7.38 (d, 1H), 7.24 (dd, 1H), 6.92 (d, 1H), 5.10 (d, 1H), 4.75(bs, 1H), 3.80 (s, 3H), 3.70 (m, 2H), 3.40 (m, 2H); LC/MS (m/z)[M+1]⁺494.0 (calculated for C₂₂H₁₈F₃N₃O₅S, 493.46).

Example 354-{4-[2-(2S,3-Dihydroxy-propylamino)-4-oxo-4H-thiazol-5-ylidenemethyl]-2-methoxy-phenoxy}-3-trifluoromethyl-benzonitrile

¹H NMR (400 Hz, DMSO) δ 8.34 (d, 1H), 8.02 (dd, 1H), 7.64 (s, 1H), 7.50(d, 1H), 7.38 (d, 1H), 7.24 (dd, 1H), 6.92 (d, 1H), 5.10 (d, 1H), 4.75(bs, 1H), 3.80 (s, 3H), 3.70 (m, 2H), 3.40 (m, 2H); LC/MS (m/z)[M+1]⁺494.1 (calculated for C₂₂H₁₈F₃N₃O₅S, 493.46).

Example 364-(2-Methoxy-4-{4-oxo-2-[2-(2-oxo-pyrrolidin-1-yl)-ethylamino]-4H-thiazol-5-ylidenemethyl}-phenoxy)-3-trifluoromethyl-benzonitrile

¹H NMR (400 Hz, CDCl₃) δ 8.34 (bs, 1H), 7.96 (d, 1H), 7.72 (s, 1H), 7.68(dd, 1H), 7.14 (m, 3H), 6.78 (d, 1H), 3.92 (m, 2H), 3.78 (s, 3H), 3.60(m, 4H), 2.44 (t, 2H), 2.12 (m, 2H); LC/MS (m/z) [M+1]⁺531.3 (calculatedfor C₂₅H₂₁F₃N₄O₄S, 530.52).

Example 374-(4-{2-[(2-Amino-ethyl)-methyl-amino]-4-oxo-4H-thiazol-5-ylidenemethyl}-2-methoxy-phenoxy)-3-trifluoromethyl-benzonitrile

¹H NMR (400 Hz, CDCl₃) δ 8.54 (bs, 1H), 8.03 (s, 1H), 7.95 (d, 1H), 7.66(dd, 1H), 7.50 (d, 1H), 7.32 (dd, 1H), 7.14 (d, 1H), 6.80 (d, 1H), 3.81(s, 3H), 3.74 (m, 2H), 3.57 (m, 2H), 3.08 (s, 3H); LC/MS (m/z)[M+1]⁺477.1 (calculated for C₂₂H₁₉F₃N₄O₃S, 476.47).

Example 384-{4-[2-(4-Ethanesulfonyl-piperazin-1-yl)-4-oxo-4H-thiazol-5-ylidenemethyl]-2-methoxy-phenoxy}-3-trifluoromethyl-benzonitrile

¹H NMR (400 Hz, CDCl₃) δ 7.97 (d, 1H), 7.80 (s, 1H), 7.68 (dd, 1H), 7.21(d, 2H), 7.16 (s, 1H), 6.77 (d, 1H), 4.20 (t, 2H), 3.80 (s, 3H), 3.75(t, 2H), 3.50 (m, 4H), 3.04 (qt, 2H), 1.40 (t, 3H); LC/MS (m/z)[M+1]⁺581.1 (calculated for C₂₅H₂₃F₃N₄O₅S₂, 580.60).

Example 394-{4-[2-(3-Hydroxy-pyrrolidin-1-yl)-4-oxo-4H-thiazol-5-ylidenemethyl]-2-methoxy-phenoxy}-3-trifluoromethyl-benzonitrile

¹H NMR (400 Hz, CDCl₃) δ 7.96 (d, 1H), 7.72 (d, 1H), 7.67 (dd, 1H), 7.14(m, 3H), 6.77 (d, 1H), 4.70 (m, 1H), 4.30 (m, 1H), 4.08 (m, 1H), 3.90(m, 1H), 3.80 (d, 3H), 3.70 (m, 2H), 2.26 (m, 2H); LC/MS (m/z)[M+1]⁺490.2 (calculated for C₂₃H₁₈F₃N₃O₄S, 489.47).

Example 404-{4-[2-(2,6-Dimethyl-morpholin-4-yl)-4-oxo-4H-thiazol-5-ylidenemethyl]-2-methoxy-phenoxy}-3-trifluoromethyl-benzonitrile

¹H NMR (400 Hz, DMSO) δ 8.34 (d, 1H), 8.02 (dd, 1H), 7.72 (s, 1H), 7.54(d, 1H), 7.39 (d, 1H), 7.32 (dd, 1H), 6.90 (d, 1H), 4.50 (dd, 1H), 3.80(m, 4H), 3.70 (m, 2H), 3.18 (m, 1H), 2.95 (m, 1H), 1.20 (t, 6H); LC/MS(m/z) [M+1]⁺518.3 (calculated for C₂₅H₂₂F₃N₃O₄S, 517.52).

Example 414-(4-{2-[Bis-(2-hydroxy-ethyl)-amino]-4-oxo-4H-thiazol-5-ylidenemethyl}-2-fluoro-phenoxy)-3-trifluoromethyl-benzonitrile

¹H NMR (400 Hz, DMSO) δ 8.40 (d, 1H), 8.10 (dd, 1H), 7.74 (dd, 1H), 7.64(s, 1H), 7.55 (m, 2H), 7.20 (d, 1H), 4.95 (t, 1H), 3.80 (t, 1H), 3.70(m, 4H), 2.50 (m, 4H); LC/MS (m/z) [M+1]⁺496.2 (calculated forC₂₂H₁₇F₄N₃O₄S, 495.45).

Example 424-{2-Fluoro-4-[4-oxo-2-(2-[1,2,4]triazol-1-yl-ethylamino)-4H-thiazol-5-ylidenemethyl]-phenoxy}-3-trifluoromethyl-benzonitrile

¹H NMR (400 Hz, DMSO) δ 8.52 (s, 1H), 8.40 (d, 1H), 8.10 (dd, 1H), 8.00(s, 1H), 7.68 (dd, 1H), 7.63 (s, 1H), 7.30 (m, 2H), 7.20 (d, 1H), 4.45(t, 2H), 3.92 (t, 2H); LC/MS (m/z) [M+1]⁺503.0 (calculated forC₂₂H₁₄F₄N₆O₂S, 502.45).

Example 43 4-{2-Fluoro-4-[2-(4-methyl-3-oxo-piperazin -1-yl)-4-oxo-4H-thiazol-5-ylidenemethyl]-phenoxy}-3-trifluoromethyl-benzonitrile

¹H NMR (400 Hz, DMSO) δ 8.40 (d, 1H), 8.10 (dd, 1H), 7.74 (m, 2H), 7.55(m, 2H), 7.20 (dd, 1H), 4.40 (s, 1H), 4.26 (s, 1H), 4.13 (t, 1H), 3.94(t, 1H), 3.50 (m, 2H), 2.89 (d, 3H); LC/MS (m/z) [M+1]⁺505.2 (calculatedfor C₂₃H₁₆F₄N₄O₃S, 504.46).

Example 444-{4-[2-(4-Ethanesulfonyl-piperazin-1-yl)-4-oxo-4H-thiazol-5-ylidenemethyl]-2-fluoro-phenoxy}-3-trifluoromethyl-benzonitrile

¹H NMR (400 Hz, CDCl₃) δ 8.01 (d, 1H), 7.76 (m, 2H), 7.40 (m, 2H), 7.28(d, 1H), 6.92 (d, 1H), 4.20 (t, 2H), 3.75 (t, 2H), 3.50 (m, 4H), 3.04(qt, 2H), 1.40 (t, 3H); LC/MS (m/z) [M+1]⁺569.2 (calculated forC₂₄H₂₀F₄N₄O₄S₂, 568.57).

Example 454-{2-Fluoro-4-[2-(3-hydroxy-pyrrolidin-1-yl)-4-oxo-4H-thiazol-5-ylidenemethyl]-phenoxy}-3-trifluoromethyl-benzonitrile

¹H NMR (400 Hz, DMSO) δ 8.42 (d, 1H), 8.12 (dd, 1H), 7.77 (dd, 1H), 7.68(s, 1H), 7.57 (m, 2H), 7.22 (d, 1H), 5.30 (dd, 1H), 4.45 (m, 1H), 3.75(m, 4H), 2.05 (m, 2H); LC/MS (m/z) [M+1]⁺478.2 (calculated forC₂₂H₁₅F₄N₃O₃S, 477.43).

Example 464-{4-[2-(2,6-Dimethyl-morpholin-4-yl)-4-oxo-4H-thiazol-5-ylidenemethyl]-2-fluoro-phenoxy}-3-trifluoromethyl-benzonitrile

¹H NMR (400 Hz, DMSO) δ 8.42 (d, 1H), 8.12 (dd, 1H), 7.76 (dd, 1H), 7.70(s, 1H), 7.58 (m, 2H), 7.20 (d, 1H), 4.50 (dd, 1H), 3.80 (dd, 1H), 3.70(m, 2H), 3.18 (m, 1H), 2.95 (m, 1H), 1.20 (t, 6H); LC/MS (m/z)[M+1]⁺506.3 (calculated for C₂₄H₁₉F₄N₃O₃S, 505.49).

Example 474-{2-Fluoro-4-[4-oxo-2-(3-oxo-piperazin-1-yl)-4H-thiazol-5-ylidenemethyl]-phenoxy}-3-trifluoromethyl-benzonitrile

¹H NMR (400 Hz, DMSO) δ 8.42 (d, 1H), 8.12 (dd, 1H), 7.76 (m, 2H), 7.58(m, 2H), 7.22 (m, 1H), 4.38 (s, 1H), 4.25 (s, 1H), 4.06 (t, 1H), 3.88(t, 1H), 3.40 (m, 2H); LC/MS (m/z) [M+1]⁺491.2 (calculated forC₂₂H₁₄F₄N₄O₃S, 490.43).

Example 484-{4-[2-(3-Dimethylamino-propylamino)-4-oxo-4H-thiazol-5-ylidenemethyl]-2-fluoro-phenoxy}-3-trifluoromethyl-benzonitrile

¹H NMR (400 Hz, CDCl₃) δ 8.12 (d, 1H), 7.76 (m, 2H), 7.42 (m, 2H), 7.30(m, 1H), 6.92 (d, 1H), 3.90 (t, 1H), 3.60 (t, 1H), 2.64 (m, 2H), 2.35(d, 6H), 1.90 (m, 2H); LC/MS (m/z) [M+1]⁺493.0 (calculated forC₂₃H₂₀F₄N₄O₂S, 492.49).

Example 494-{2-Fluoro-4-[2-(3-morpholin-4-yl-propylamino)-4-oxo-4H-thiazol-5-ylidenemethyl]-phenoxy}-3-trifluoromethyl-benzonitrile

¹H NMR (400 Hz, CDCl₃) δ 7.97 (d, 1H), 7.76 (m, 2H), 7.42 (m, 3H), 6.94(d, 1H), 3.85 (m, 6H), 2.70 (m, 6H), 1.95 (m, 2H); LC/MS (m/z)[M+1]⁺535.2 (calculated for C₂₅H₂₂F₄N₄O₃S, 534.53).

Example 50 4-(4-{2-[(2,3-Dihydroxy-propyl)-methyl-amino]-4-oxo-4H-thiazol-5-ylidenemethyl}-2-fluoro-phenoxy)-3-trifluoromethyl-benzonitrile

¹H NMR (400 Hz, CDCl₃) δ 8.01 (d, 1H), 7.75 (dd, 1H), 7.70 (s, 1H), 7.38(m, 2H), 7.26 (d, 1H), 6.91 (d, 1H), 4.16 (bs, 1H), 3.98 (dd, 1H), 3.89(m, 1H), 3.79 (bs, 1H), 3.66 (m, 3H), 3.41 (s, 3H); LC/MS (m/z)[M+1]⁺496.2 (calculated for C₂₂H₁₇F₄N₃O₄S, 495.45).

Example 51 4-(2-Fluoro-4-{4-oxo-2-[3-(2-oxo-pyrrolidin-1-yl)-propylamino]-4H-thiazol-5-ylidenemethyl}-phenoxy)-3-trifluoromethyl-benzonitrile

¹H NMR (400 Hz, DMSO) δ 8.42 (d, 1H), 8.12 (dd, 1H), 7.70 (m, 2H), 7.54(m, 2H), 7.22 (d, 1H), 3.50 (t, 2H), 3.34 (m, 2H), 3.25 (t, 2H), 2.22(t, 2H), 1.94 (m, 2H), 1.80 (m, 2H); LC/MS (m/z) [M+1]⁺533.2 (calculatedfor C₂₅H₂₀F₄N₄O₃S, 532.51).

Example 521-{5-[3-Methoxy-4-(4-methoxycarbonyl-2-trifluoromethyl-phenoxy)-benzylidene]-4-oxo-4,5-dihydro-thiazol-2-yl}-azetidine-3-carboxylicacid

¹H NMR (400 Hz, CD₃OD) δ 8.30 (d, 1H), 8.12 (dd, 1H), 7.76 (s, 1H), 7.36(d, 1H), 7.28 (m, 2H), 6.80 (d, 1H), 4.60 (m, 4H), 3.85 (dd, 7H); LC/MS(m/z) [M+1]⁺537.2 (calculated for C₂₄H₁₉F₃N₂O₇S, 536.48).

Example 534-{4-[2-(3-Hydroxy-piperidin-1-yl)-4-oxo-4H-thiazol-5-ylidenemethyl]-2-methoxy-phenoxy}-3-trifluoromethyl-benzoicacid methyl ester

¹H NMR (400 Hz, CDCl₃) δ 8.34 (t, 1H), 8.06 (dd, 1H), 7.72 (d, 1H), 7.14(m, 3H), 6.74 (m, 1H), 4.10 (m, 3H), 3.92 (d, 3H), 3.80 (d, 3H), 3.55(m, 2H), 2.05 (m, 2H), 1.80 (m, 2H); LC/MS (m/z) [M+1]⁺537.2 (calculatedfor C₂₅H₂₃F₃N₂O₆S, 536.52).,

Example 54 4-{2-Methoxy-4-[4-oxo-2-(3-oxo-piperazin-1-yl)-4H-thiazol-5-ylidenemethyl]-phenoxy}-3-trifluoromethyl-benzoic acid methylester

¹H NMR (400 Hz, CDCl₃) δ 8.37 (d, 1H), 8.07 (dd. 1H), 7.82 (s, 1H), 7.18(m, 3H), 6.84 (bs, 1H), 6.75 (d, 1H), 4.65 (s, 1H), 4.30 (s, 2H), 3.92(m, 3H), 3.82 (m, 4H), 3.62 (m, 2H); LC/MS (m/z) [M+1]⁺536.2 (calculatedfor C₂₄H₂₀F₃N₃O₆S, 535.49).

Example 551-{5-[4-(4-Cyano-2-trifluoromethyl-phenoxy)-3-ethoxy-benzylidene]-4-oxo-4,5-dihydro-thiazol-2-yl}-azetidine-3-carboxylicacid

¹H NMR (400 Hz, CD₃OD) δ 8.10 (d, 1H), 7.84 (dd, 1H), 7.73 (s, 1H), 7.32(m, 3H), 6.90 (d, 1H), 4.55 (m, 4H), 4.05 (qt, 2H), 3.70 (m, 1H), 1.15(t, 3H); LC/MS (m/z) [M+1]⁺518.2 (calculated for C₂₄H₁₈F₃N₃O₅S, 517.48).

Example 564-(4-{2-[Bis-(2-hydroxy-ethyl)-amino]-4-oxo-4H-thiazol-5-ylidenemethyl}-2-ethoxy-phenoxy)-3-trifluoromethyl-benzonitrile

¹H NMR (400 Hz, CDCl₃) δ 7.96 (d, 1H), 7.74 (s, 1H), 7.66 (dd, 1H), 7.18(m, 2H), 7.10 (d, 1H), 6.78 (d, 1H), 4.15 (t, 2H), 4.00 (m, 6H), 3.76(t, 2H), 1.20 (t, 3H); LC/MS (m/z) [M+1]⁺522.2 (calculated forC₂₄H₂₂F₃N₃O₅S, 521.51).

Example 57 4-{2-Ethoxy-4-[4-oxo-2-(3-oxo-piperazin-1-yl)-4H-thiazol-5-ylidenemethyl]-phenoxy}-3-trifluoromethyl-benzonitrile

¹H NMR (400 Hz, CDCl₃) δ 7.97 (d, 1H), 7.82 (s, 1H), 7.68 (dd, 1H), 7.24(m, 2H), 7.14 (d, 1H), 7.02 (bs, 1H), 6.81 (d, 1H), 4.65 (s, 1H), 4.30(s, 2H), 4.02 (m, 2H), 3.88 (t, 1H), 3.65 (d, 2H), 1.20 (t, 3H); LC/MS(m/z) [M+1]⁺517.2 (calculated for C₂₄H₁₉F₃N₄O₄S, 516.49).

Example 58 5-[4-(2,4-Bis-trifluoromethyl-phenoxy)-3-methoxy-benzylidene]-2-(3-hydroxy-piperidin-1-yl)-thiazol-4-one

¹H NMR (400 Hz, CDCl₃) δ 7.92 (s, 1H), 7.74 (d, 1H), 7.64 (d, 1H), 7.16(m, 3H), 6.79 (m, 1H), 4.08 (m, 1H), 3.80 (m, 5H), 3.55 (m, 2H), 2.04(m, 2H), 1.75 (m, 2H); LC/MS (m/z) [M+1]⁺547.4 (calculated forC₂₄H₂₀F₆N₂O₄S, 546.48).

Example 594-{5-[4-(2,4-Bis-trifluoromethyl-phenoxy)-3-methoxy-benzylidene]-4-oxo-4,5-dihydro-thiazol-2-yl}-piperazin-2-one

¹H NMR (400 Hz, CDCl₃) δ 7.94 (d, 1H), 7.84 (d, 1H), 7.65 (dd, 1H), 7.18(m, 3H), 6.80 (d, 1H), 4.68 (s, 1H), 4.30 (s, 2H), 3.86 (m, 4H), 3.62(m, 2H); LC/MS (m/z) [M+1]⁺546.4 (calculated for C₂₃H₁₇F₆N₃O₄S, 545.46).

Example 605-[4-(4-Chloro-2-trifluoromethyl-phenoxy)-3-methoxy-benzylidene]-2-[2-(2-oxo-pyrrolidin-1-yl)-ethylamino]-thiazol-4-one

¹H NMR (400 Hz, DMSO) δ 7.83 (d, 1H), 7.63 (m, 2H), 7.44 (d, 1H), 7.24(m, 2H), 6.84 (d, 1H), 3.81 (s, 3H), 3.66 (t, 2H), 3.42 (m, 4H), 2.17(t, 2H), 1.90 (m, 2H); LC/MS (m/z) [M+1]⁺540.2 (calculated forC₂₄H₂₁ClF₃N₃O₄S, 539.96).

Example 614-{5-[4-(4-Chloro-2-trifluoromethyl-phenoxy)-3-methoxy-benzylidene]-4-oxo-4,5-dihydro-thiazol-2-yl}-piperazin-2-one

¹H NMR (400 Hz, DMSO) δ 8.40 (m, 1H), 7.83 (d, 1H), 7.72 (d, 1H), 7.63(m, 1H), 7.50 (dd, 1H), 7.28 (m, 2H), 6.84 (m, 1H), 4.37 (s, 1H), 4.24(s, 1H), 4.06 (m, 1H), 3.84 (m, 4H), 3.40 (m, 2H); LC/MS (m/z)[M+1]⁺512.2 (calculated for C₂₂H₁₇ClF₃N₃O₄S, 511.90).

Example 625-[4-(4-Chloro-2-trifluoromethyl-phenoxy)-3-methoxy-benzylidene]-2-[(2,3-dihydroxy-propyl)-methyl-amino]-thiazol-4-one

¹H NMR (400 Hz, DMSO) δ 7.83 (d, 1H), 7.65 (m, 2H), 7.50 (dd, 1H), 7.27(m, 2H), 6.84 (dd, 1H), 5.24 (d, 1H), 5.06 (d, 1H), 4.86 (t, 1H), 4.76(t, 1H), 3.90 (m, 1H), 3.80 (d, 3H), 3.30 (d, 3H); LC/MS (m/z)[M+1]⁺517.2 (calculated for C₂₂H₂₀ClF₃N₂O₅S, 516.92).

Example 633-Chloro-4-(2-methoxy-4-{4-oxo-2-[2-(2-oxo-pyrrolidin-1-yl)-ethylamino]-4H-thiazol-5-ylidenemethyl}-phenoxy)-benzonitrile

¹H NMR (400 Hz, CDCl₃) δ 7.76 (m, 2H), 7.45 (dd, 1H), 7.20 (m, 1H), 7.10(d, 2H), 6.76 (d, 1H), 3.93 (m, 2H), 3.82 (s, 3H), 3.60 (m, 4H), 2.44(t, 2H), 2.12 (m, 2H); LC/MS (m/z) [M+1]⁺497.2 (calculated forC₂₄H₂₁ClN₄O₄S, 496.97).

Example 64 3-Chloro-4-{2-methoxy-4-[4-oxo-2-(3-oxo-piperazin -1-yl)-4H-thiazol-5-ylidenemethyl]-phenoxy}-benzonitrile

¹H NMR (400 Hz, CDCl₃) δ 7.82 (d, 1H), 7.78 (d, 1H), 7.43 (dd, 1H), 7.19(m, 3H), 6.76 (d, 1H), 4.30 (m, 3H), 3.82 (d, 4H), 3.62 (m, 3H); LC/MS(m/z) [M+1]⁺469.2 (calculated for C₂₂H₁₇ClN₄O₄S, 468.91).

Example 653-Chloro-4-(4-{2-[(2,3-dihydroxy-propyl)-methyl-amino]-4-oxo-4H-thiazol-5-ylidenemethyl}-2-methoxy-phenoxy)-benzonitrile

¹H NMR (400 Hz, CDCl₃) δ 7.76 (m, 2H), 7.44 (dd, 1H), 7.14 (m, 3H), 6.73(d, 1H), 4.14 (bs, 1H), 3.98 (dd, 1H), 3.88 (m, 1H), 3.83 (s, 3H), 3.65(m, 4H), 3.40 (s, 3H); LC/MS (m/z) [M+1]⁺474.2 (calculated forC₂₂H₂₀ClN₃O₅S, 473.93).

Example 664-{5-[4-(4-Chloro-2-trifluoromethyl-phenoxy)-3-fluoro-benzylidene]-4-oxo-4,5-dihydro-thiazol-2-yl}-piperazin-2-one

¹H NMR (400 Hz, DMSO) δ 8.40 (d, 1H), 7.97 (d, 1H), 7.74 (m, 3H), 7.55(m, 1H), 7.40 (m, 1H), 7.18 (dd, 1H), 4.40 (s, 1H), 4.26 (s, 1H), 4.05(t,1H), 3.85 (t, 1H), 3.40 (m, 2H); LC/MS (m/z) [M+1]⁺500.2 (calculatedfor C₂₁H₁₄ClF₄N₃O₃S, 499.87)

Example 675-[4-(4-Chloro-2-trifluoromethyl-phenoxy)-3-fluoro-benzylidene]-2-[3-(2-oxo-pyrrolidin-1-yl)-propylamino]-thiazol-4-one

¹H NMR (400 Hz, DMSO) δ 7.97 (d, 1H), 7.70 (m, 3H), 7.40 (m, 2H), 7.18(dd, 1H), 3.50 (t, 2H), 3.34 (m, 2H), 3.24 (t, 2H), 2.22 (t, 2H), 1.93(m, 2H), 1.80 (m, 2H); LC/MS (m/z) [M+1]⁺542.2 (calculated forC₂₄H₂₀ClF₄N₃O₃S, 541.95).

Example 682-{5-[4-(4-Cyano-2-trifluoromethyl-phenoxy)-3-methoxy-benzylidene]-4-oxo-4,5-dihydro-thiazol-2-ylamino}-3-hydroxy-propionicacid methyl ester

¹H NMR (400 Hz, DMSO) δ 7.97 (d, 1H), 7.83 (1H, s), 7.68 (dd, 1H),7.22-7.12 (m, 3H), 6.77 (d, 1H), 6.0 (bs, 1H), 4.38-4.13 (m, 3H), 3.87(s, 3H), 3.82 (s, 3H) LC/MS (m/z) [M+1]⁺522.1 (calculated forC₂₃H₁₈F₃N₃O₆S, 521.47).

Example 694-(4-{2-[2-(2-Hydroxy-ethoxy)-ethylamino]-4-oxo-4H-thiazol-5-ylidenemethyl}-2-methoxy-phenoxy)-3-trifluoromethyl-benzonitrile

¹H NMR (400 Hz, CDCl₃) δ 7.96 (dd, 1H), 7.75 (d, 1H), 7.67 (dd, 1H), 7.2(s, 1H), 7.14-7.11 (m, 2H), 6.76 (dd, 1H), 3.94-3.65 (m, 11H)

LC/MS (m/z) [M+1]⁺508.1 (calculated for C₂₃H₂₀F₃N₃O₅S, 508.48).

Example 704-{4-[2-(2-Imidazol-1-yl-ethylamino)-4-oxo-4H-thiazol-5-ylidenemethyl]-2-methoxy-phenoxy}-3-trifluoromethyl-benzonitrile

¹H NMR (400 MHz, CDCl₃) δ 10.95 (bs, 1H), 7.95 (d, 1H), 7.73 (s, 1H),7.67 (dd, 1H), 7.26 (m, 1H), 7.20-7.08 (m, 4H), 6.88 (d, 1H), 6.76 (d,1H), 4.32 (m, 2H), 4.03 (m, 2H), 3.77 (s, 3H);

LC/MS (m/z) [M+1]⁺514.1 (calculated for C₂₄H₁₈F₃N₅O₃S, 513.49).

Example 71N-(2-{5-[4-(4-Cyano-2-trifluoromethyl-phenoxy)-3-methoxy-benzylidene]-4-oxo-4,5-dihydro-thiazol-2-ylamino}-ethyl)-acetamide

¹H NMR (400 MHz, CDCl₃) δ 11.1 (bs, 1H), 8.2 (m, 1H), 7.97 (d, 1H), 7.80(s, 1H), 7.68 (dd, 1H), 7.24 (m, 1H), 7.18 (m, 1H), 6.76 (d, 1H), 3.84(s, 3H) (m, 4H), 2.02 (s, 3H)

LC/MS (m/z) [M+1]⁺505.1 (calculated for C₂₃H₁₉F₃N₄O₄S, 504.48).

Example 72 4-{2-Methoxy-4-[4-oxo-2-(2-[1 2,4]triazol-1-yl-ethylamino)-4H-thiazol-5-ylidenemethyl]-phenoxy}-3-trifluoromethyl-benzonitrile

¹H NMR (400 MHz, CDCl₃) δ 8.24 (s, 1H), 8.13 (s, 1H), 7.98-7.96 (m, 4H),7.79 (s, 1H), 7.75 (s, 1H), 7.70-7.65 (m, 2H), 7.22-7.11 (m, 6H);6.79-6.75 (m, 2H); 4.87-4.85 (m, 2H), 4.55-4.52 (m, 2H), 4.22-4.19 (m,2H), 4.0-3.98 (m, 2H), 3.84 (s, 3H), 3.79 (s, 3H);

LC/MS (m/z) [M+1]⁺515.0 (calculated for C₂₃H₁₇F₃N₆O₃S, 514.48).

Example 734-{2-Methoxy-4-[2-(3-morpholin-4-yl-3-oxo-propylamino)-4-oxo-4H-thiazol-5-ylidenemethyl]-phenoxy}-3-trifluoromethyl-benzonitrile

¹H NMR (400 MHz, CDCl₃) δ 7.97-7.96 (m, 2H), 7.77 (s, 1H), 7.72 (s, 1H),7.70-7.65 (m, 2H), 7.31-7.28 (m, 1H), 7.24-7.12 (m, 5H), 6.78-6.76 (m,2H); 4.05-4.01 (m, 2H), 3.83 (s, 3H), 3.80 (s, 3H); 3.73-3.59 (m, 16),3.46-3.44 (m, 2H), 3.10-3.07 (m, 2H), 2.73-2.70 (m, 2H);

LC/MS (m/z) [M+1]⁺561.0 (calculated for C₂₆H₂₃F₃N₄O₅S, 560.65).

Example 74(2-{5-[4-(4-Cyano-2-trifluoromethyl-phenoxy)-3-methoxy-benzylidene]-4-oxo-4,5-dihydro-thiazol-2-ylamino}-ethyl)-urea

¹H NMR (400 MHz, DMSO) δ 8.30 (d, 1H), 7.98 (dd, 1H), 7.56 (s, 1H),7.47-7.44 (m, 1H), 7.35-7.28 (m, 1H), 7.21 (dd, 1H), 6.89 (d, 1H), 6.1(bs, 1H), 5.52 (bs, 2H), 3.77 (s, 3H), 3.51-3.47 (m, 2H), 3.19-3.15 (m,2H)

LC/MS (m/z) [M+1]⁺505.9 (calculated for C₂₂H₁₈F₃N₅O₄S, 505.47).

Example 754-{2-Methoxy-4-[2-(methoxy-methyl-amino)-4-oxo-4H-thiazol-5-ylidenemethyl]-phenoxy}-3-trifluoromethyl-benzonitrile

¹H NMR (400 MHz, CDCl₃) δ 7.96 (d, 1H), 7.82 (s, 1H), 7.67 (dd, 1H),7.21 (m, 2H), 7.16 (d, 1H), 6.77 (d, 1H), 3.92 (s, 3H), 3.82 (s, 3H);3.63 (s, 3H)

LC/MS (m/z) [M+1]⁺464.0 (calculated for C₂₁H₁₆F₃N₃O₄S, 463.43).

Example 76{5-[4-(4-Cyano-2-trifluoromethyl-phenoxy)-3-methoxy-benzylidene]-4-oxo-4,5-dihydro-thiazol-2-ylamino}-aceticacid

¹H NMR (400 MHz, DMSO) δ 13.0 (bs, 1H), 10.0-9-98 (m, 1H), 8.31 (s, 1H),8.01-7.97 (m, 1H), 7.67 (s, 1H), 7.51 (dd, 1H), 7.37 (d, 1H), 7.24 (dd,1H), 1H), 4.26 (d, 2H), 3.77 (s, 3H)

LC/MS (m/z) [M+1]⁺478.1 (calculated for C₂₁H₁₄F₃N₃O₅S, 477.41).

Example 774-[2-Methoxy-4-(2-methylamino-4-oxo-4H-thiazol-5-ylidenemethyl)-phenoxy]-3-trifluoromethyl-benzonitrile

¹H NMR (400 MHz, DMSO) δ 9.62 (bs, 1H), 8.31 (s, 1H), 7.90 (dd, 1H),7.64 (s, 1H), 7.46 (d, 1H), 7.37-7.34 (m, 1H), 7.22 (dd, 1H), 6.89 (d,1H), 3.77 (s, 3H), 3.06 (s, 3H)

LC/MS (m/z) [M+1]⁺434.1 (calculated for C₂₀H₁₄F₃N₃O₃S, 433.40).

Example 781-{5-[4-(4-Cyano-2-trifluoromethyl-phenoxy)-3-methoxy-benzylidene]-4-oxo-4,5-dihydro-thiazol-2-yl}-piperidine-4-carboxylicacid amide

¹H NMR (400 MHz, DMSO) δ 8.31 (d, 1H), 7.99 (dd, 1H), 7.68 (s, 1H), 7.51(d, 1H), 7.37-7.29 (m, 2H), 6.88 (d, 1H), 4.55-4.52 (m, 1H), 3.87-3.84(m, 1H), 3.78 (s, 3H), 3.50-3.44 (m, 1H), 3.36-3.32 (m, 2H), 1.92-1.85(m, 2H), 1.63-1.59 (m, 2H)

LC/MS (m/z) [M+1]⁺531.3 (calculated for C₂₅H₂₁F₃N₄O₄S, 530.52).

Example 791-{5-[4-(4-Cyano-2-trifluoromethyl-phenoxy)-3-methoxy-benzylidene]-4-oxo-4,5-dihydro-thiazol-2-yl}-piperidine-4-carboxylicacid methyl ester

¹H NMR (400 MHz, CDCl₃) δ 7.96 (d, 1H), 7.78 (s, 1H), 7.68 (dd, 1H),7.21-7.20 (m, 2H), 7.16 (m, 1H), 6.77 (d, 1H), 4.69-4.63 (m, 1H),3.88-3.83 (m, 1H), 3.81 (s, 3H), 3.74 (s, 3H), 3.57-3.43 (m, 2H),2.76-2.70 (m, 1H), 2.15-2.08 (m, 2H), 1.98-1.87 (m, 2H)

LC/MS (m/z) [M+1]⁺546.3 (calculated for C₂₆H₂₂F₃N₃O₅S, 545.53).

Example 804-(2-Methoxy-4-{2-[(morpholin-2-ylmethyl)-amino]-4-oxo-4H-thiazol-5-ylidenemethyl}-phenoxy)-3-trifluoromethyl-benzonitrile

2-({5-[4-(4-Cyano-2-trifluoromethyl-phenoxy)-3-methoxy-benzylidene]-4-oxo-4,5-dihydro-thiazol-2-ylamino}-methyl)-morpholine-4-carboxylicacid tert-butyl ester was prepared using4-[2-Methoxy-4-(2-methylsulfanyl-4-oxo-4H-thiazol-5-ylidenemethyl)-phenoxy]-3-trifluoromethyl-benzonitrileand 2-aminomethyl-morpholine-4-carboxylic acid tert-butyl ester asdescribed in Example 5C.

LC/MS (m/z) [M+1]⁺618.8 (calculated for C₂₉H₂₉F₃N₄O₆S, 618.63).2-({5-[4-(4-Cyano-2-trifluoromethyl-phenoxy)-3-methoxy-benzylidene]-4-oxo-4,5-dihydro-thiazol-2-ylamino}-methyl)-morpholine-4-carboxylicacid tert-butyl ester (0.1 g, 0.16 mmol) was dissolved in drydichloromethane (6 mL). To the reaction mixture was then added at 0° C.trifluoroacetic acid (2 mL). The reaction mixture was stirred at 0° C.for 1 hour and then at room temperature for 30 minutes. The reactionmixture was then partitioned with saturated aqueous sodium bicarbonateand dichloromethane. The organic layer was washed with brine, dried withNa₂SO₄, filtered and the solvent evaporated in vacuo to yield a crudeoil. The crude oil was purified via flash chromatography (6% ammonia 2.0M methanol/dichloromethane) to yield the compound as a solid (0.052 g,63%).

¹H NMR (400 MHz, CDCl₃) δ 7.96 (s, 1H), 7.78 (d, 1H), 7.68-7.77 (m, 1H),7.21-7.14 (m, 3H), 6.77 (d, 1H), 6.39 (bs, 1H), 4.04-4.0 (m, 1H),3.92-3.89 (m, 1H), 3.81 (s, 3H), 3.75-3.45 (m, 3H), 2.99-2.86 (m, 3H),2.70-2.60 (m, 1H)

LC/MS (m/z) [M+1]⁺519.2 (calculated for C₂₄H₂₁F₃N₄O₄S, 518.51).

Example 814-[4-(2-Dimethylamino-4-oxo-4H-thiazol-5-ylidenemethyl)-2-methoxy-phenoxy]-3-trifluoromethyl-benzonitrile

¹H NMR (400 MHz, DMSO) δ 8.31 (d, 1H), 7.99 (dd, 1H), 7.67 (s, 1H), 7.51(d, 1H), 7.37-7.35 (m, 1H), 7.30 (dd, 1H), 6.88 (d, 1H), 3.77 (s, 3H),3.25 (s, 3H), 3.15 (d, 3H)

LC/MS (m/z) [M+1]⁺448.0 (calculated for C₂₁H₁₆F₃N₃O₃S, 447.43).

Example 824-{5-[4-(4-Cyano-2-trifluoromethyl-phenoxy)-3-methoxy-benzylidene]-4-oxo-4,5-dihydro-thiazol-2-ylamino}-butyricacid methyl ester

¹H NMR (400 MHz, DMSO) δ 8.30 (s, 1H), 7.99 (dd, 1H), 7.41 (s, 0.5H),7.34 (d, 0.5H), 7.26-7.24 (m, 1.5H), 7.18-7.14 (m, 1.5H), 6.88 (dd, 1H),3.76 (s, 3H), 3.58 (s, 3H), 3.24-3.20 (m, 2H), 2.39-2.32 (m, 2H),1.78-1.70 (m, 2H)

LC/MS (m/z) [M+1]⁺520.1 (calculated for C₂₄H₂₀F₃N₃O₅S, 519.49).

Example 83(1-{5-[4-(4-Cyano-2-trifluoromethyl-phenoxy)-3-methoxy-benzylidene]-4-oxo-4,5-dihydro-thiazol-2-yl}-piperidin-4-yl)-aceticacid methyl ester

¹H NMR (400 MHz, CDCl₃) δ 7.96 (d, 1H), 7.77 (s, 1H), 7.67 (dd, 1H),7.21-7.19 (m, 2H), 7.16 (m, 1H), 6.77 (d, 1H), 4.99-4.96 (m, 1H),3.87-3.82 (m, 1H), 3.80 (s, 3H), 3.70 (s, 3H), 3.44-3.37 (m, 1H),3.22-3.15 (m, 1H), 2.34-2.31 (m, 2H), 2.23-2.14 (m, 1H), 2.03-1.99 (m,1H), 1.94-1.90 (m, 1H), 1.45-1.34 (m, 2H)

LC/MS (m/z) [M+1]⁺560.3 (calculated for C₂₇H₂₄F₃N₃O₅S, 559.56).

Example 84{5-[4-(4-Cyano-2-trifluoromethyl-phenoxy)-3-methoxy-benzylidene]-4-oxo-4,5-dihydro-thiazol-2-ylamino}-aceticacid methyl ester

¹H NMR (400 MHz, CDCl₃) δ 7.96 (m, 1H), 7.81 (s, 1H), 7.67 (dd, 1H),7.21-7.17 (m, 2H), 7.14-7.13 (m, 1H), 6.77 (d, 1H), 6.52 (bs, 1H), 4.50(d, 2H), 2.23-3H), 3.81 (s, 3H)

LC/MS (m/z) [M+1]⁺492.1 (calculated for C₂₂H₁₆F₃N₃O₅S, 491.44).

Example 854-{4-[2-(3,5-Difluoro-benzylamino)-4-oxo-4H-thiazol-5-ylidenemethyl]-2-methoxy-phenoxy}-3-trifluoromethyl-benzonitrile

¹H NMR (400 MHz, DMSO) δ 10.17 (bs, 1H), 8.33 (m, 1H), 8.01 (dd, 1H),7.71 (s, 1H), 7.50 (d, 1H), 7.38 (d, 1H), 7.28-7.19 (m, 2H), 7.11-7.0(m, 2H), 6.91 (d, 1H), 4.78 (d, 2H), 3.80 (s, 3H)

LC/MS (m/z) [M+1]⁺546.2 (calculated for C₂₆H₁₆F₅N₃O₃S, 545.48).

Example 864-{4-[2-(4-Dimethylamino-piperidin-1-yl)-4-oxo-4H-thiazol-5-ylidenemethyl]-2-methoxy-phenoxy}-3-trifluoromethyl-benzonitrile

¹H NMR (400 MHz, DMSO) δ 8.34 (d, 1H), 8.02 (dd, 1H), 7.70 (s, 1H), 7.52(d, 1H), 7.39-7.36 (m, 1H), 7.32 (dd, 1H), 6.90 (dd, 1H), 4.58-4.53 (m,1H), 3.89-3.86 (m, 1H), 3.80 (s, 3H), 3.50-3.43 (m, 1H), 3.38-3.30 (m,2H), 1.94-1.86 (m, 2H), 1.53-1.47 (m, 2H)

LC/MS (m/z) [M+1]⁺531.2 (calculated for C₂₆H₂₅F₃N₄O₃S, 530.56).

Example 874-{4-[2-(2-Amino-ethylamino)-4-oxo-4H-thiazol-5-ylidenemethyl]-2-methoxy-phenoxy}-3-trifluoromethyl-benzonitrileHCl salt

(2-{5-[4-(4-Cyano-2-trifluoromethyl-phenoxy)-3-methoxy-benzylidene]-4-oxo-4,5-dihydro-thiazol-2-ylamino}-ethyl)-carbamicacid tert-butyl ester was prepared using4-[2-Methoxy-4-(2-methylsulfanyl-4-oxo-4H-thiazol-5-ylidenemethyl)-phenoxy]-3-trifluoromethyl-benzonitrileand (2-Amino-ethyl)-carbamic acid tert-butyl ester as described inExample 5C.

LC/MS (m/z) [M+1]⁺563.1 (calculated for C₂₆H₂₅F₃N₄O₅S, 562.56).(2-{5-[4-(4-Cyano-2-trifluoromethyl-phenoxy)-3-methoxy-benzylidene]-4-oxo-4,5-dihydro-thiazol-2-ylamino}-ethyl)-carbamicacid tert-butyl ester (0.09 g, 0.14 mmol) was dissolved in a 5/3 mixtureof ethyl acetate/methanol (6 mL). To the reaction was then added aqueous4.ON HCl (4 mL). The reaction mixture was stirred at room temperaturefor 2 days and the solvent evaporated in vacuo to yield a crude oil.Diethyl ether was added to the residue and the solvent evaporated invacuo to give a solid which was recrystallized from MeOH and diethylether to yield compound as a solid (0.020 g, 30%).

¹H NMR (400 MHz, CD₃OD) δ 8.11 (d, 1H), 7.83 (dd, 1H), 7.80 (s, 1H),7.37(s, 1H), 7.30-7.28 (m, 2H), 6.86 (d, 1H), 3.89-3.85 (m, 2H), 3.82(s, 3H), 3.26-3.22 (m, 2H)

LC/MS (m/z) [M+1]⁺463.0 (calculated for C₂₁H₁₇F₃N₄O₃S, 462.45).

Example 884-(4-{2-[(Furan-3-ylmethyl)-amino]-4-oxo-4H-thiazol-5-ylidenemethyl}-2-methoxy-phenoxy)-3-trifluoromethyl-benzonitrile

¹H NMR (400 MHz, DMSO) δ 9.98 (bs, 1H), 8.33 (d, 1H), 8.01 (dd, 1H),7.72-7.67 (m, 2H), 7.50 (d, 1H), 7.39-7.36 (m, 1H), 7.25 (dd, 1H), 6.91(d, 1H), 6.53 (bs, 1H), 4.59 (s 2H), 3.79 (s, 3H)

LC/MS (m/z) [M+1]⁺500.0 (calculated for C₂₄H₁₆F₃N₃O₄S, 499.46).

Example 894-(2-Methoxy-4-{4-oxo-2-[(thiophen-3-ylmethyl)-amino]-4H-thiazol-5-ylidenemethyl}-phenoxy)-3-trifluoromethyl-benzonitrile

¹H NMR (400 MHz, DMSO) δ 10.06 (bs, 1H), 8.30 (d, 1H), 7.98 (dd, 1H),7.66 (s, 1H), 7.54 (dd, 1H), 7.47-7.44 (m, 2H), 7.34 (d, 1H), 7.10 (dd,1H), 6.88 (d, 1H), 4.71 (s 2H), 3.76 (s, 3H)

LC/MS (m/z) [M+1]⁺516.0 (calculated for C₂₄H₁₆F₃N₃O₃S₂, 515.53).

Example 904-{4-[2-(3-Fluoro-pyrrolidin-1-yl)-4-oxo-4H-thiazol-5-ylidenemethyl]-2-methoxy-phenoxy}-3-trifluoromethyl-benzonitrile

¹H NMR (400 MHz, DMSO) δ 7.96 (d, 1H), 7.80 (m, 1H), 7.67 (dd, 1H),7.21-7.20 (m, 2H), 7.16 (m, 1H), 7.79-7.76 (m, 1H), 5.52-5.48 (m, 0.5H),5.39-5.35 (m, 0.5H), 4.02-3.77 (m, 3H), 3.81 (s, 3H), 2.58-2.46 (m, 1H),2.35-2.16 (m, 1H)

LC/MS (m/z) [M+1]⁺492.0 (calculated for C₂₃H₁₇F₄N₃O₃S, 491.46).

Example 914-{4-[2-(2-Fluoro-ethylamino)-4-oxo-4H-thiazol-5-ylidenemethyl]-2-methoxy-phenoxy}-3-trifluoromethyl-benzonitrile

¹H NMR (400 MHz, CDCl₃) δ 7.97 (s, 1.5H), 7.82 (s, 1H), 7.77 (s, 0.5H),0.68-7.65 (m, 1.5H), 7.22-7.13 (m, 4.5H), 6.77 (d, 1.5H), 6.22 (bs, 1H),4.86-4.84 (m, 0.5H), 4.76-4.72 (m, 2H), 4.64-4.61 (m, 1H), 4.11-4.08 (m,1H), 4.04-4.00 (m, 1H), 3.82-3.81 (m, 4.5H), 3.78-3.74 (0.5H)

LC/MS (m/z) [M+1]⁺466.2 (calculated for C₂₁H₁₅F₄N₃O₃S, 465.42).

Example 924-{4-[2-(2,2-Difluoro-ethylamino)-4-oxo-4H-thiazol-5-ylidenemethyl]-2-methoxy-phenoxy}-3-trifluoromethyl-benzonitrile

¹H NMR (400 MHz, DMSO) δ 8.33 (d, 1H), 8.01 (dd, 1H), 7.15 (s, 1H), 7.51(d, 1H), 7.40-7.30 (m, 1H), 7.26 (dd, 1H), 6.92 (d, 1H), 6.43-6.41 (m,0.25H) 6.29-6.26 (m, 0.5H), 6.15-6.13 (m, 0.25H), 4.06-3.97 (m, 2H),3.80 (s, 3H)

LC/MS (m/z) [M+1]⁺484.0 (calculated for C₂₁H₁₄F₅N₃O₃S, 483.41).

Example 934-{4-[2-(3-Fluoro-pyrrolidin-1-yl)-4-oxo-4H-thiazol-5-ylidenemethyl]-2-methoxy-phenoxy}-3-trifluoromethyl-benzonitrile

¹H NMR (400 MHz, DMSO) δ 8.34 (s, 1H), 8.06-7.96 (m, 1H), 7.73 (s, 1H),7.55 (bs., 1H), 7.39 (d, 1H), 7.31 (d, 1H), 6.91 (d, 1H), 5.59-5.56 (m,0.5H), 5.46-5.43 (m, 0.5H), 4.11-3.83 (m, 3H), 3.83-3.75 (m, 4H),2.42-2.18 (m, 2H)

LC/MS (m/z) [M+1]⁺492.0 (calculated for C₂₃H₁₇F₄N₃O₃S, 491.46).

Example 94 4-{2-Methoxy-4-[2-(4-methyl-3-oxo-piperazin-1-yl)-4-oxo-4H-thiazol-5-ylidenemethyl]-phenoxy}-3-trifluoromethyl-benzonitrile

¹H NMR (400 MHz, DMSO) δ 8.34 (d, 1H), 8.01 (dd, 1H), 7.75 (d, 1H), 7.53(dd, 1H), 7.40-7.31 (m, 2H), 6.91 (d, 1H), 4.42 (s, 1H), 4.29 (s, 1H),4.16-4.13 (m, 1H), 3.97-3.94 (m, 1H), 3.80 (s, 3H), 3.54-3.48 (m, 2H),2.91 (s, 3H)

LC/MS (m/z) [M+1]⁺517.0 (calculated for C₂₄H₁₉F₃N₄O₄S, 516.49).

Example 95 4-{4-[2-(3-Amino-2-hydroxy-propylamino)-4-oxo-4H-thiazol-5-ylidenemethyl]-2-methoxy-phenoxy}-3-trifluoromethyl-benzonitrile

¹H NMR (400 MHz, CD₃OD) δ 8.08 (s, 1H), 7.80 (d, 1H), 7.74 (s, 1H), 7.34(s, 1H), 7.29-7.23 (m, 2H), 6.83 (d, 1H), 4.09-4.02 (m, 1H), 3.80-3.69(m, 5H), 3.58 (dd, 2H), 3.07 (m, 1H), 2.85 (m, 1H)

LC/MS (m/z) [M+1]⁺493.1 (calculated for C₂₂H₁₉F₃N₄O₄S, 492.47).

Example 964-{2-Fluoro-4-[2-(2-fluoro-ethylamino)-4-oxo-4H-thiazol-5-ylidenemethyl]-2-fluoro-phenoxy}-3-trifluoromethyl-benzonitrile

¹H NMR (400 MHz, CDCl₃) δ 7.98 (s, 1H), 7.73 (d, 1H), 7.69 (s, 1H),7.40-7.32 (m, 2H), 7.26-7.22 (m, 1H), 6.89 (d, 1H), 4.68 (t, 1H), 4.56(t, 1H), 3.96 (t, 0.85H), 3.89 (t, 0.85H), 3.72 (t, 0.15H), 3.67 (t,0.15H)

LC/MS (m/z) [M+1]⁺454.1 (calculated for C₂₀H₁₂F₅N₃O₂S, 453.39).

Example 974-{4-[2-(2,2-Difluoro-ethylamino)-4-oxo-4H-thiazol-5-ylidenemethyl]-2-fluoro-phenoxy}-3-trifluoromethyl-benzonitrile

¹H NMR (400 MHz, DMSO) δ 8.42 (s, 1H), 8.15-8.09 (m, 1H), 7.76-7.70 (m,1H), 7.69 (s, 1H), 7.59-7.49 (m, 2H), 7.23 (d, 1H), 6.43-6.41 (m, 0.25H)(m, 0.5H), 6.15-6.14 (m, 1H), 4.06-3.98 (m, 2H)

LC/MS (m/z) [M+1]⁺472.1 (calculated for C₂₀H₁₁F₆N₃O₂S, 471.38).

Example 984-{2-Fluoro-4-[4-oxo-2-(2-[1,2,4]triazol-1-yl-ethylamino)-4H-thiazol-5-ylidenemethyl]-phenoxy}-3-trifluoromethyl-benzonitrile

¹H NMR (400 MHz, CDCl₃) δ 8.22 (s, 1H), 8.12 (s, 1H), 8.05-7.93 (m, 4H),7.80-7.68 (m, 4H), 7.44-7.23 (m, 7H), 6.97-6.86 (m, 1H), 4.84 (t, 4H),(m, 2H), 4.26-4.17 (m, 2H), 4.00 (t, 4H)

LC/MS (m/z) [M+1]⁺503.0 (calculated for C₂₂H₁₄F₄N₆O₂S, 502.45).

Example 99 4-(2-Fluoro-4-{4-oxo-2-[2-(3-oxo-piperazin-1-yl)-ethylamino]-4H-thiazol-5-ylidenemethyl}-phenoxy)-3-trifluoromethyl-benzonitrile

¹H NMR (400 MHz, CDCl₃) δ 8.04-7.98 (m, 1H), 7.79-7.71 (m, 2H),7.53-7.23 (m, 4H), 6.96-6.88 (m, 1H), 6.37 (br. s., 1H), 3.90-3.82 (m,1H), 3.59 (t, 1H), 3.46-3.36 (m, 2H), 3.29-3.20 (m, 2H), 2.90 (t, 1H),2.83-2.71 (m, 4H)

LC/MS (m/z) [M+1]⁺534.1 (calculated for C₂₄H₁₉F₄N₅O₃S, 533.50).

Example 100 4-(2-Fluoro-4-{4-oxo-2-[3-(3-oxo-piperazin-1-yl)-propylamino]-4H-thiazol-5-ylidenemethyl}-phenoxy)-3-trifluoromethyl-benzonitrile

¹H NMR (400 MHz, CDCl₃) δ 8.01 (br. s., 1H), 7.79-7.70 (m, 2H),7.46-7.25 (m, 4H), 6.92 (dd, 1H), 3.86 (d, 1H), 3.60 (t, 1H), 3.47-3.38(m, 2H), 3.22 (d, 2H), 2.75 (t, 1H), 2.60-2.72 (m, 3H), 2.01 (t, 1H),1.97-1.87 (m, 1H)

LC/MS (m/z) [M+1]⁺548.1 (calculated for C₂₅H₂₁F₄N₅O₃S, 547.53).

Example 1014-(2-Methoxy-4-{4-oxo-2-[3-(3-oxo-piperazin-1-yl)-propylamino]-4H-thiazol-5-ylidenemethyl}-phenoxy)-3-trifluoromethyl-benzonitrile

¹H NMR (400 MHz, CDCl₃) δ 7.97 (s, 1H), 7.78 (d, 1H), 7.68 (d, 1H),7.09-7.32 (m, 4H), 6.78 (d, 1H), 3.87 (q, 1H), 3.84-3.76 (m, 3H), 3.59(t, 1H), 3.39-3.54 (m, 3H), 3.22 (d, 2H), 2.76 (t, 1H), 2.73-2.60 (m,3H), 2.0 (t, 1H), 1.94-1.89 (m, 1H)

LC/MS (m/z) [M+1]⁺560.1 (calculated for C₂₆H₂₄F₃N₅0₄S, 559.56).

Example 1024-{4-[2-(3-Hydroxy-piperidin-1-yl)-4-oxo-4H-thiazol-5-ylidenemethyl]-2-methoxy-phenoxy}-3-trifluoromethyl-benzonitrile

¹H NMR (400 MHz, CDCl₃) δ 7.96 (s, 1H), 7.75 (d, 1H), 7.70-7.65 (m, 1H),7.20-7.17 (m, 2H), 7.15 (s, 1H), 6.77 (dd, 1H), 4.12-3.99 (m, 2H), 3.81(s, 3H), 3.78-3.47 (m, 2H), 2.17-1.91 (m, 3H), 1.90-1.78 (m, 1H),1.75-1.60 (m, 1H)

LC/MS (m/z) [M+1]⁺504.2 (calculated for C₂₄H₂₀F₃N₃O₄S, 503.49).

Example 1034-{2-Fluoro-4-[2-(3-hydroxy-piperidin-1-yl)-4-oxo-4H-thiazol-5-ylidenemethyl]-phenoxy}-3-trifluoromethyl-benzonitrile

¹H NMR (400 MHz, CDCl₃) δ 8.01 (s, 1H), 7.78-7.71 (m, 2H), 7.44-7.37 (m,2H), 7.30-7.25 (m, 1H), 6.91 (d, 1H), 4.17-3.99 (m, 3H), 3.69-3.48 (m,2H), 2.17-1.92 (m, 3H), 1.92-1.77 (m, 1H), 1.77-1.65 (m, 1H)

LC/MS (m/z) [M+1]⁺492.2 (calculated for C₂₃H₁₇F₄N₃O₃S, 491.46).

Example 1044-(2-Fluoro-4-{2-[2-(4-methyl-piperazin-1-yl)-ethylamino]-4-oxo-4H-thiazol-5-ylidenemethyl}-phenoxy)-3-trifluoromethyl-benzonitrile

¹H NMR (400 MHz, CDCl₃) δ 8.01 (s, 1H), 7.78-7.73 (m, 2H), 7.43-7.35 (m,2H), 7.31-7.28 (m, 1H), 6.91 (d, 1H), 3.81 (t, 2H), 3.55-3.49 (m, 2H),2.73 (t, 2H), 2.68 (t, 2H), 2.58-2.48 (m., 4H), 2.33 (s, 3H)

LC/MS (m/z) [M+1]⁺534.2 (calculated for C₂₅H₂₃F₄N₅O₂S, 533.54).

Example 1054-(2-Methoxy-4-{4-oxo-2-[2-(3-oxo-piperazin-1-yl)-ethylamino]-4H-thiazol-5-ylidenemethyl}-phenoxy)-3-trifluoromethyl-benzonitrile

¹H NMR (400 MHz, CDCl₃) δ 7.97 (br. s., 1H), 7.81-7.76 (m, 1H), 7.68 (d,1H), 7.24-7.13 (m, 3H), 7.03 (bs., 1H), 6.81-6.75 (m, 1H), 3.89-3.77 (m,4H), 3.58 (t, 1H), 3.47-3.37 (m, 2H), 3.29-3.20 (m, 2H), 2.91 (t, 1H),2.83-2.72 (m, 4H)

LC/MS (m/z) [M+1]⁺546.1 (calculated for C₂₅H₂₂F₃N₅O₄S, 545.33).

Example 1061-{5-[4-(4-Cyano-2-trifluoromethyl-phenoxy)-3-methoxy-benzylidene]-4-oxo-4,5-dihydro-thiazol-2-yl}-azetidine-3-carboxylicacid

¹H NMR (400 MHz, CD₃OD) δ 7.59 (s, 1H), 7.33 (dd, 1H), 7.24 (s, 1H),6.85 (s, 1H), 6.78 (s, 2H), 6.36 (d, 1H), 4.13-3.95 (m, 4H), 3.26-3.22(m, 1H)

LC/MS (m/z) [M+1]⁺504.0 (calculated for C₂₃H₁₆F₃N₃O₅S, 503.45).

Example 107 4-(2-Methoxy-4-{4-oxo-2-[(1 H-tetrazol-5-ylmethyl)-amino]-4H-thiazol-5-ylidenemethyl}-phenoxy)-3-trifluoromethyl-benzonitrile

¹H NMR (400 MHz, CD₃OD) δ 7.59 (s, 1H), 7.36-7.30 (m, 1H), 7.27 (s, 1H),6.85 (s, 1H), 6.78 (s, 2H), 6.36 (d, 1H), 4.62 (bs., 2H), 3.31 (s, 3H)

LC/MS (m/z) [M+1]⁺501.9 (calculated for C₂₁H₁₄F₃N₇O₃S, 501.44).

Example 108 4-(2-Fluoro-4-{4-oxo-2-[(1H-tetrazol-5-ylmethyl)-amino]-4H-thiazol-5-ylidenemethyl}-phenoxy)-3-trifluoromethyl-benzonitrile

¹H NMR (400 MHz, CD₃OD) δ 8.18 (s, 1H), 7.91-7.97 (m, 1H), 7.75 (s, 1H),7.60-7.49 (m, 2H), 7.46-7.38 (m, 1H), 7.10 (d, 1H), 5.14 (s, 2H)

LC/MS (m/z) [M+1]⁺489.9 (calculated for C₂₀H₁₁F₄N₇O₂S, 489.41).

Example 1094-(2-Methoxy-4-{4-oxo-2-[2-(tetrahydro-pyran-4-yl)-ethylamino]-4H-thiazol-5-ylidenemethyl}-phenoxy)-3-trifluoromethyl-benzonitrile

¹H NMR (400 MHz, CDCl₃) δ 8.02 (bs, 1H), 7.86-7.78 (m, 1H), 7.75-7.68(m, 7.31 (s, 1H), 7.26-7.14 (m, 2H), 6.85-6.78 (m, 1H), 4.02 (dd, 2H),3.89-3.82 (m, 3H), 3.59 (t, 2H), 3.50-3.36 (m, 2H), 1.93 (q, 2H),1.81-1.65 (m, 4H), 1.51-1.35 (m, 2H)

LC/MS (m/z) [M+1]⁺532.2 (calculated for C₂₆H₂₄F₃N₃O₄S, 531.55).

Example 1104-(2-Fluoro-4-{4-oxo-2-[2-(tetrahydro-pyran-4-yl)-ethylamino]-4H-thiazol-5-ylidenemethyl}-phenoxy)-3-trifluoromethyl-benzonitrile

¹H NMR (400 MHz, CDCl₃) δ 8.01 (m, 1H), 7.79-7.71 (m, 2H), 7.47-7.28 (m,3H), 6.96-6.89 (m, 1H), 4.03-3.95 (m, 2H), 3.56 (t, 2H), 3.40 (t, 2H),1.90 (q, 2H), 1.76-1.62 (m, 4H), 1.47-1.33 (m, 2H)

LC/MS (m/z) [M+1]⁺520.2 (calculated for C₂₅H₂₁F₄N₃O₃S, 519.51).

Example 111 4-(4-{2-[1-(2-Hydroxy-ethyl)-piperidin-4-ylamino]-4-oxo-4H-thiazol-5-ylidenemethyl}-2-methoxy-phenoxy)-3-trifluoromethyl-benzonitrile

¹H NMR (400 MHz, CDCl₃) δ 7.97 (d, 1H), 7.77 (s, 1H), 7.71-7.64 (m, 1H),7.22 (s. 1H), 7.18-7.11 (m, 2H), 6.81-6.74 (m, 1H), 4.33-4.30 (m, 1H),3.85-3.78 (m, 3H), 3.73-3.67 (m, 2H), 3.51-3.42 (m, 1H), 3.11-3.09 (m,2H), 2.73-2.62 (m, 2H), 2.45-2.26 (m, 2H), 2.26-2.12 (m, 2H), 1.88-1.80(m., 1H)

LC/MS (m/z) [M+1]⁺547.0 (calculated for C₂₆H₂₅F₃N₄O₄S, 546.56).

Example 1124-(2-Fluoro-4-{2-[1-(2-hydroxy-ethyl)-piperidin-4-ylamino]-4-oxo-4H-thiazol-5-ylidenemethyl}-phenoxy)-3-trifluoromethyl-benzonitrile

¹H NMR (400 MHz, CDCl₃) δ 8.01 (d, 1H), 7.78-7.72 (m, 2H), 7.47-7.28 (m,3H), 6.92 (dd, 1H), 4.33-4.28 (m, 1H), 3.71-3.63 (m, 2H), 3.52-3.42 (m,1H), 3.14-3.00 (m, 2H), 2.68-2.59 (m, 2H), 2.36-2.28 (m, 2H), 2.24-2.10(m, 2H), 2.08-1.99 (m, 2H), 1.82-1.74 (m 1H)

LC/MS (m/z) [M+1]⁺535.2 (calculated for C₂₅H₂₂F₄N₄O₃S, 534.53).

Example 1131-{5-[3-Methoxy-4-(4-methoxycarbonyl-2-trifluoromethyl-phenoxy)-benzylidene]-4-oxo-4,5-dihydro-thiazol-2-yl)-piperidine-4-carboxylicacid methyl ester

¹H NMR (400 MHz, CDCl₃) δ 8.37 (d, 1H), 8.07 (dd, 1H), 7.80 (s, 1H),7.20-3H), 6.75 (d, 1H), 4.69-4.64 (m, 1H), 3.93 (s, 3H), 3.89-3.82 (m,4H), 3H), 3.59-3.41 (m, 2H), 2.79-2.67 (m, 1H), 2.15-2.09 (m, 2H),1.99-1.85 (m, 2H)

LC/MS (m/z) [M+1]⁺579.3 (calculated for C₂₇H₂₅F₃N₂O₇S, 578.56).

Example 1144-{4-[2-(3-Hydroxy-piperidin-1-yl)-4-oxo-4H-thiazol-5-ylidenemethyl]-2-methoxy-phenoxy}-3-trifluoromethyl-benzamide

¹H NMR (400 MHz, CD₃OD) δ 8.25 (d, 1H), 7.98 (dd, 1H), 7.72 (d, 1H),7.32 (s, 1H), 7.28 (d, 1H), 7.22 (d, 1H), 6.77 (d, 1H), 4.17 (dd, 1H),4.00-3.90 (m, 2), 3.87-3.73 (m, 4H), 3.71-3.56 (m, 1H), 3.50 (dd, 1H),2.06-1.96 (m, 1H), 1.80-1.59 (m, 2H)

LC/MS (m/z) [M+1]⁺522.3 (calculated for C₂₄H₂₂F₃N₃O₅S, 521.51).

Example 115 4-{2-Methoxy-4-[4-oxo-2-(3-oxo-piperazin-1-yl)-4H-thiazol-5-ylidenemethyl]-phenoxy}-3-trifluoromethyl-benzamide

¹H NMR (400 MHz, CD₃OD) δ 8.22 (s, 1H), 7.97 (dd, 1H), 7.76 (d, 1H),7.35 (s, 1H), 7.32-7.27 (m, 1H), 7.26-7.20 (m, 1H), 6.76 (d, 1H), 4.51(s, 1H), 4.31 (s, 1H), 4.20-4.14 (m, 1H), 3.94-3.88 (m, 1H), 3.81 (s,3H), 3.53-3.46 (m, 2H)

LC/MS (m/z) [M+1]⁺521.0 (calculated for C₂₃H₁₉F₃N₄O₅S, 520.48).

Example 1161-{5-[4-(4-Cyano-2-trifluoromethyl-phenoxy)-3-fluoro-benzylidene]-4-oxo-4,5-dihydro-thiazol-2-yl}-azetidine-3-carboxylicacid

¹H NMR (400 MHz, CD₃OD) δ 8.13 (s, 1H), 7.91 (dd, 1H), 7.67 (s, 1H),7.55-7.46 (m, 2H), 7.42-7.35 (m, 1H), 7.06 (d, 1H), 4.60-4.53 (m, 4H),3.62 (bs., 1H)

LC/MS (m/z) [M+1]⁺492.2 (calculated for C₂₂H₁₃F₄N₃O₄S, 491.42).

Example 1172-[Bis-(2-hydroxy-ethyl)-amino]-5-[4-(2,4-bis-trifluoromethyl-phenoxy)-3-methoxy-benzylidene]-thiazol-4-one

¹H NMR (400 MHz, CDCl₃) δ 8.08 (s, 1H), 7.99-7.88 (m, 2H), 7.59 (s, 1H),7.45-7.32 (m, 2H), 6.98 (d, 1H), 3.82 (s, 3H), 3.35 (s, 4H), 2.85 (s,4H)

LC/MS (m/z) [M+1]⁺551.2 (calculated for C₂₃H₂₀F₆N₂O₅S, 550.47).

Example 1181-{5-[4-(2-Isopropyl-phenoxy)-benzylidene]-4-oxo-4,5-dihydro-thiazol-2-yl}-azetidine-3-carboxylicacid

A. 4-(2-Isopropyl-phenoxy)-benzaldehyde

To a mixture of 4-fluoro-benzaldehyde (1.5 g, 12.08 mmol) and2-isopropyl-phenol (1.64 g, 12.08 mmol) in anhydrous N,N-dimethylacetamide (20 mL) was added granulated potassium carbonate (3.7 g, 26.58mmol). The reaction mixture was stirred at 150° C. for 18 hours and waspartitioned between ethyl acetate and brine. The ethyl acetate layer waswashed with saturated aqueous hydrogenocarbonate solution, brine, driedover Na₂SO₄, filtered, and the solvent evaporated in vacuo to yield acrude oil. The crude oil was purified via flash chromatography (15%ethyl acetate in n-heptane) to yield4-(2-Isopropyl-phenoxy)-benzaldehyde as a gum (2.25g, 77%).

¹H NMR (400 MHz, CDCl₃) δ 9.91 (s, 1H), 7.83 (d, 2H), 7.45-7.33 (m, 1H),7.30-7.10 (m, 2H), 7.07-9.96 (m, 3H), 3.15 (dt, 1H), 1.20 (d, 6H)

LC/MS (m/z) [M+1]⁺241.2 (calculated for C₁₆H₁₆O₂, 240.30).

B. 5-[4-(2-Isopropyl-phenoxy)-benzylidene]-2-thioxo-thiazolidin-4-one

The title compound was prepared using rhodanine and4-(2-Isopropyl-phenoxy)-benzaldehyde according to General Procedure B.

¹H NMR (400 MHz, DMSO) δ 7.68-7.55 (m, 3H), 7.46 (dd, 1H), 7.33-7.20 (m,2H), 7.02 (d, 3H), 3.11-3.04 (m, 1H), 1.15 (d, 6H)

LC/MS (m/z) [M+1]⁺356.1 (calculated for C₁₉H₁₇NO₂S₂, 355.48).

C.5-[4-(2-Isopropyl-phenoxy)-benzylidene]-2-methylsulfanyl-thiazol-4-one

To a solution of5-[4-(2-Isopropyl-phenoxy)-benzylidene]-2-thioxo-thiazolidin-4-one (0.4g, 1.12 mmol) in Ethanol (14 mL) was added CH₃l (0.32 g, 2.25 mmol) anddiisopropylethylamine (0.17 g, 1.35 mmol). The reaction mixture wasstirred at room temperature for 4 h. It was then added water (40 mL) andthe slurry was stirred at room temperature for 30 minutes. The solid wasfiltered, washed with water to yield the5-[4-(2-Isopropyl-phenoxy)-benzylidene]-2-methylsulfanyl-thiazol-4-oneas a yellow solid (0.42 g, 94%)

¹H NMR (400 MHz, DMSO) δ 7.82 (s, 1H), 7.68 (d, 2H), 7.46 (dd, 1H),7.31-7.23 (m, 2H), 7.02 (d, 3H), 3.12-3.05 (m, 1H), 2.82 (s, 3H), 1.15(d, 6H)

LC/MS (m/z) [M+1]⁺370.0 (calculated for C₂₀H₁₉NO₂S₂, 369.50).

D.1-{5-[4-(2-Isopropyl-phenoxy)-benzylidene]-4-oxo-4,5-dihydro-thiazol-2-yl}-azetidine-3-carboxylicacid was prepared from5-[4-(2-Isopropyl-phenoxy)-benzylidene]-2-methylsulfanyl-thiazol-4-oneand azetidine-3-carboxylic acid and substituting MeCN with DMF asdescribed in Example 5C

¹H NMR (400 MHz, CD₃OD) δ 7.72 (s, 1H), 7.57-7.52 (m, 2H), 7.46-7.40 (m,1H), 7.27-7.22 (m, 2H), 7.03-6.96 (m, 3H), 4.64-4.48 (m, 4H), 3.72-3.61(m, 1H), 3.25-3.18 (m, 1H), 1.24 (d, 7H)

LC/MS (m/z) [M+1]⁺423.1 (calculated for C₂₃H₂₂N₂O₄S, 422.50).

Example 1191-{5-[3-Methoxy-4-(2-trifluoromethyl-phenoxy)-benzylidene]-4-oxo-4,5-dihydro-thiazol-2-yl}-azetidine-3-carboxylicacid

A. 3-Methoxy-4-(2-trifluoromethyl-phenoxy)-benzaldehyde was preparedfrom 4-fluoro-3-methoxy-benzaldehyde and 2-trifluoromethyl-phenol asdescribed in Example XXXA

¹H NMR (400 MHz, CDCl₃) δ 9.94 (s, 1H), 7.71 (d, 1H), 7.55 (d, 1H),7.51-2H), 7.23 (t, 1H), 7.02 (d, 1H), 6.89 (d, 1H), 3.92 (s, 3H)

LC/MS (m/z) [M+1]⁺296.2 (calculated for C₁₅H₁₁F₃O₃, 296.24).

B.5-[3-Methoxy-4-(2-trifluoromethyl-phenoxy)-benzylidene]-2-thioxo-thiazolidin-4-onewas prepared according to General Procedure B

¹H NMR (400 MHz, DMSO) δ 7.77 (d, 1H), 7.69 (s, 1H), 7.60 (t, 1H),7.50-7.43 (m, 1H), 7.34-7.10 (m, 5H), 6.87 (d, 1H), 3.83 (s, 3H)

LC/MS (m/z) [M+1]⁺412.0 (calculated for C₁₈H₁₂F₃NO₃S₂, 411.42).

C.5-[3-Methoxy-4-(2-trifluoromethyl-phenoxy)-benzylidene]-2-methylsulfanyl-thiazol-4-onewas prepared from5-[3-Methoxy-4-(2-trifluoromethyl-phenoxy)-benzylidene]-2-thioxo-thiazolidin-4-oneand CH₃1 according to Example XXXC

¹H NMR (400 MHz, DMSO) δ 7.90 (s, 1H), 7.79-7.75 (m, 1H), 7.63-7.56 (m,1H), 7.55-7.51 (m, 1H), 7.34-7.24 (m, 2H), 7.15-7.21 (m, 1H), 6.87 (d,1H), 3.80-2.83 (s, 3H), 2.84 (s, 3H)

LC/MS (m/z) [M+1]⁺426.0 (calculated for C₁₉H₁₄F₃NO₃S₂, 425.45).

D.1-{5-[3-Methoxy-4-(2-trifluoromethyl-phenoxy)-benzylidene]-4-oxo-4,5-dihydro-thiazol-2-yl}-azetidine-3-carboxylicacid was prepared from5-[3-Methoxy-4-(2-trifluoromethyl-phenoxy)-benzylidene]-2-methylsulfanyl-thiazol-4-oneand azetidine-3-carboxylic acid and substituting MeCN with DMF asdescribed in Example 5C

¹H NMR (400 MHz, CD₃OD) δ 7.82 (s, 1H), 7.71 (s, 1H), 7.67 (d, 1H),7.50-7.43 (m, 1H), 7.27 (s, 1H), 7.24-7.14 (m, 2H), 7.09 (d, 1H), 6.77(d, 1H), 4.60-4.53 (m, 4H), 3.84 (s, 3H), 3.66-3.64 (bs, 1H)

LC/MS (m/z) [M+1]⁺479.1 (calculated for C₂₂H₁₇F₃N₂O₅S, 478.44).

D) General Administration, Formulation, and Dosages

The present compounds are ERR-α inverse agonists and are thereforeuseful in treating, preventing, or inhibiting the progression of ERR-αmediated conditions including but not limited to ankylosing spondylitis,artherosclerosis, arthritis (such as rheumatoid arthritis, infectiousarthritis, childhood arthritis, psoriatic arthritis, reactivearthritis), bone-related diseases (including those related to boneformation), breast cancer (including those unresponsive to anti-estrogentherapy), cardiovascular disorders, cartilage-related disease (such ascartilage injury/loss, cartilage degeneration, and those related tocartilage formation), chondrodysplasia, chondrosarcoma, chronic backinjury, chronic bronchitis, chronic inflammatory airway disease, chronicobstructive pulmonary disease, diabetes, disorders of energyhomeostasis, gout, pseudogout, lipid disorders, metabolic syndrome,multiple myeloma, obesity, osteoarthritis, osteogenesis imperfecta,osteolytic bone metastasis, osteomalacia, osteoporosis, Paget's disease,periodontal disease, polymyalgia rheumatica, Reiter's syndrome,repetitive stress injury, hyperglycemia, elevated blood glucose level,and insulin resistance and other disorders, diseases, or conditionsrelated thereto.

The invention features a method for treating a subject with an ERR-αmediated disease, said method comprising administering to the subject atherapeutically effective amount of a pharmaceutical compositioncomprising a compound of the invention. In particular, the inventionalso provides a method for treating or inhibiting the progression ofbreast cancer, arthritis, inflammatory airway disease, or metabolicdisorders, and associated symptoms or complications thereof in asubject, wherein the method comprises administering to the subject atherapeutically effective amount of a pharmaceutical compositioncomprising a compound of the invention.

The present invention includes within its scope prodrugs of thecompounds of this invention. In general, such prodrugs will befunctional derivatives of the compounds which are readily convertible invivo into the required compound. Thus, in the methods of treatment ofthe present invention, the term “administering” shall encompass thetreatment of the various disorders described with the compoundspecifically disclosed or with a compound which may not be specificallydisclosed, but which converts to the specified compound in vivo afteradministration to the subject. Conventional procedures for the selectionand preparation of suitable prodrug derivatives are described, forexample, in “Design of Prodrugs”, ed. H. Bundgaard, Elsevier, 1985.

Some of the crystalline forms for the compounds may exist as polymorphsand as such are intended to be included in the present invention. Inaddition, some of the compounds may form solvates with water (i.e.,hydrates) or common organic solvents, and such solvates are intended tobe encompassed within the scope of this invention.

Where the processes for the preparation of the compounds according tothe invention give rise to mixtures of stereoisomers, these isomers maybe separated by conventional techniques such as preparativechromatography. The compounds may be prepared in racemic form or asindividual enantiomers or diasteromers by either stereospecificsynthesis or by resolution. The compounds may, for example, be resolvedinto their component enantiomers or diastereomers by standardtechniques, such as the formation of stereoisomeric pairs by saltformation with an optically active base, followed by fractionalcrystallization and regeneration of the free acid. The compounds mayalso be resolved by formation of stereoisomeric esters or amides,followed by chromatographic separation and removal of the chiralauxiliary. Alternatively, the compounds may be resolved using a chiralHPLC column. It is to be understood that all stereoisomers, racemicmixtures, diastereomers, cis-trans isomers, and enantiomers thereof areencompassed within the scope of the present invention.

E) Use

1. Dosages

Those of skill in the treatment of disorders, diseases, or conditionsmediated by ERR-α can determine the effective daily amount from the testresults presented hereinafter and other information. The exact dosageand frequency of administration depends on the particular compound ofinvention used, the particular condition being treated, the severity ofthe condition being treated, the age, weight and general physicalcondition of the particular patient as well as other medication thepatient may be taking, as is well known to those skilled in the art.Furthermore, it is evident that said effective daily amount may belowered or increased depending on the response of the treated patientand/or depending on the evaluation of the physician prescribing thecompounds of the instant invention. The effective daily amount rangesmentioned herein are therefore only guidelines in practicing the presentinvention.

Preferably, the method for the treatment of the ERR-α disordersdescribed in the present invention using any of the compounds as definedherein, the dosage form will contain a pharmaceutically acceptablecarrier containing between from about 0.1 mg to about 5000 mg;particularly from about 0.5 mg to about 1000 mg; and, more particularly,from about 1 mg to about 100 mg of the compound, and may be constitutedinto any form suitable for the mode of administration selected. Thedosages, however, may be varied depending upon the requirement of thesubjects, the severity of the condition being treated and the compoundbeing employed. The use of either daily administration or post-periodicdosing may be employed.

The pharmaceutical compositions herein will contain, per unit dosageunit, e.g., tablet, capsule, powder, injection, suppository, teaspoonfuland the like, of from about 0.001 mg/kg/day to about 10 mg/kg/day(particularly from about 0.01 mg/kg/day to about 1 mg/kg/day; and, moreparticularly, from about 0.1 mg/kg/day to about 0.5 mg/kg/day) and maybe given at a dosage of from about 0.001 mg/kg/day to about 30 mg/kg/day(particularly from about 0.01 mg/kg/day to about 2 mg/kg/day, moreparticularly from about 0.1 mg/kg/day to about 1 mg/kg/day and even moreparticularly from about 0.5 mg/kg/day to about 1 mg/kg/day).

Preferably these compositions are in unit dosage forms from such astablets, pills, capsules, dry powders for reconstitution or inhalation,granules, lozenges, sterile parenteral solutions or suspensions, meteredaerosol or liquid sprays, drops, ampoules, autoinjector devices orsuppositories for administration by oral, intranasal, sublingual,intraocular, transdermal, parenteral, rectal, vaginal, dry powderinhaler or other inhalation or insufflation means. Alternatively, thecomposition may be presented in a form suitable for once-weekly oronce-monthly administration; for example, an insoluble salt of theactive compound, such as the decanoate salt, may be adapted to provide adepot preparation for intramuscular injection.

For preparing solid pharmaceutical compositions such as tablets, theprincipal active ingredient is mixed with a pharmaceutical carrier, e.g.conventional tableting ingredients such as diluents, binders, adhesives,disintegrants, lubricants, antiadherents and gildants. Suitable diluentsinclude, but are not limited to, starch (i.e. corn, wheat, or potatostarch, which may be hydrolized), lactose (granulated, spray dried oranhydrous), sucrose, sucrose-based diluents (confectioner's sugar;sucrose plus about 7 to 10 weight percent invert sugar; sucrose plusabout 3 weight percent modified dextrins; sucrose plus invert sugar,about 4 weight percent invert sugar, about 0.1 to 0.2 weight percentcornstarch and magnesium stearate), dextrose, inositol, mannitol,sorbitol, microcrystalline cellulose (i.e. AVICEL™ microcrystallinecellulose available from FMC Corp.), dicalcium phosphate, calciumsulfate dihydrate, calcium lactate trihydrate and the like. Suitablebinders and adhesives include, but are not limited to acacia gum, guargum, tragacanth gum, sucrose, gelatin, glucose, starch, and cellulosics(i.e. methylcellulose, sodium carboxymethylcellulose, ethylcellulose,hydroxypropylmethylcellulose, hydroxypropylcellulose, and the like),water soluble or dispersible binders (i.e. alginic acid and saltsthereof, magnesium aluminum silicate, hydroxyethylcellulose [i.e.TYLOSE™ available from Hoechst Celanese], polyethylene glycol,polysaccharide acids, bentonites, polyvinylpyrrolidone,polymethacrylates and pregelatinized starch) and the like. Suitabledisintegrants include, but are not limited to, starches (corn, potato,etc.), sodium starch glycolates, pregelatinized starches, clays(magnesium aluminum silicate), celluloses (such as crosslinked sodiumcarboxymethylcellulose and microcrystalline cellulose), alginates,pregelatinized starches (i.e. corn starch, etc.), gums (i.e. agar, guar,locust bean, karaya, pectin, and tragacanth gum), cross-linkedpolyvinylpyrrolidone and the like. Suitable lubricants and antiadherentsinclude, but are not limited to, stearates (magnesium, calcium andsodium), stearic acid, talc waxes, stearowet, boric acid, sodiumchloride, DL-leucine, carbowax 4000, carbowax 6000, sodium oleate,sodium benzoate, sodium acetate, sodium lauryl sulfate, magnesium laurylsulfate and the like. Suitable gildants include, but are not limited to,talc, cornstarch, silica (i.e. CAB-O-SIL™ silica available from Cabot,SYLOID™ silica available from W. R. Grace/Davison, and AEROSIL™ silicaavailable from Degussa) and the like. Sweeteners and flavorants may beadded to chewable solid dosage forms to improve the palatability of theoral dosage form. Additionally, colorants and coatings may be added orapplied to the solid dosage form for ease of identification of the drugor for aesthetic purposes. These carriers are formulated with thepharmaceutical active to provide an accurate, appropriate dose of thepharmaceutical active with a therapeutic release profile.

Generally these carriers are mixed with the pharmaceutical active toform a solid preformulation composition containing a homogeneous mixtureof the pharmaceutical active form of the present invention, or apharmaceutically acceptable salt thereof. Generally the preformulationwill be formed by one of three common methods: (a) wet granulation, (b)dry granulation and (c) dry blending. When referring to thesepreformulation compositions as homogeneous, it is meant that the activeingredient is dispersed evenly throughout the composition so that thecomposition may be readily subdivided into equally effective dosageforms such as tablets, pills and capsules. This solid preformulationcomposition is then subdivided into unit dosage forms of the typedescribed above containing from about 0.1 mg to about 500 mg of theactive ingredient of the present invention. The tablets or pillscontaining the novel compositions may also be formulated in multilayertablets or pills to provide a sustained or provide dual-releaseproducts. For example, a dual release tablet or pill can comprise aninner dosage and an outer dosage component, the latter being in the formof an envelope over the former. The two components can be separated byan enteric layer, which serves to resist disintegration in the stomachand permits the inner component to pass intact into the duodenum or tobe delayed in release. A variety of materials can be used for suchenteric layers or coatings, such materials including a number ofpolymeric materials such as shellac, cellulose acetate (i.e. celluloseacetate phthalate, cellulose acetate trimetllitate), polyvinyl acetatephthalate, hydroxypropyl methylcellulose phthalate, hydroxypropylmethylcellulose acetate succinate, methacrylate and ethylacrylatecopolymers, methacrylate and methyl methacrylate copolymers and thelike. Sustained release tablets may also be made by film coating or wetgranulation using slightly soluble or insoluble substances in solution(which for a wet granulation acts as the binding agents) or low meltingsolids a molten form (which in a wet granulation may incorporate theactive ingredient). These materials include natural and syntheticpolymers waxes, hydrogenated oils, fatty acids and alcohols (i.e.beeswax, carnauba wax, cetyl alcohol, cetylstearyl alcohol, and thelike), esters of fatty acids metallic soaps, and other acceptablematerials that can be used to granulate, coat, entrap or otherwise limitthe solubility of an active ingredient to achieve a prolonged orsustained release product.

The liquid forms in which the novel compositions of the presentinvention may be incorporated for administration orally or by injectioninclude, but are not limited to aqueous solutions, suitably flavoredsyrups, aqueous or oil suspensions, and flavored emulsions with edibleoils such as cottonseed oil, sesame oil, coconut oil or peanut oil, aswell as elixirs and similar pharmaceutical vehicles. Suitable suspendingagents for aqueous suspensions, include synthetic and natural gums suchas, acacia, agar, alginate (i.e. propylene alginate, sodium alginate andthe like), guar, karaya, locust bean, pectin, tragacanth, and xanthangum, cellulosics such as sodium carboxymethylcellulose, methylcellulose,hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropyl celluloseand hydroxypropyl methylcellulose, and combinations thereof, syntheticpolymers such as polyvinyl pyrrolidone, carbomer (i.e.carboxypolymethylene), and polyethylene glycol; clays such as bentonite,hectorite, attapulgite or sepiolite; and other pharmaceuticallyacceptable suspending agents such as lecithin, gelatin or the like.Suitable surfactants include but are not limited to sodium docusate,sodium lauryl sulfate, polysorbate, octoxynol-9, nonoxynol-10,polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 80,polyoxamer 188, polyoxamer 235 and combinations thereof. Suitabledeflocculating or dispersing agent include pharmaceutical gradelecithins. Suitable flocculating agent include but are not limited tosimple neutral electrolytes (i.e. sodium chloride, potassium, chloride,and the like), highly charged insoluble polymers and polyelectrolytespecies, water soluble divalent or trivalent ions (i.e. calcium salts,alums or sulfates, citrates and phosphates (which can be used jointly informulations as pH buffers and flocculating agents). Suitablepreservatives include but are not limited to parabens (i.e. methyl,ethyl, n-propyl and n-butyl), sorbic acid, thimerosal, quaternaryammonium salts, benzyl alcohol, benzoic acid, chlorhexidine gluconate,phenylethanol and the like. There are many liquid vehicles that may beused in liquid pharmaceutical dosage forms, however, the liquid vehiclethat is used in a particular dosage form must be compatible with thesuspending agent(s). For example, nonpolar liquid vehicles such as fattyesters and oils liquid vehicles are best used with suspending agentssuch as low HLB (Hydrophile-Lipophile Balance) surfactants,stearalkonium hectorite, water insoluble resins, water insoluble filmforming polymers and the like. Conversely, polar liquids such as water,alcohols, polyols and glycols are best used with suspending agents suchas higher HLB surfactants, clays silicates, gums, water solublecellulosics, water soluble polymers and the like. For parenteraladministration, sterile suspensions and solutions are desired. Liquidforms useful for parenteral administration include sterile solutions,emulsions and suspensions. Isotonic preparations which generally containsuitable preservatives are employed when intravenous administration isdesired.

Furthermore, compounds of the present invention can be administered inan intranasal dosage form via topical use of suitable intranasalvehicles or via transdermal skin patches, the composition of which arewell known to those of ordinary skill in that art. To be administered inthe form of a transdermal delivery system, the administration of atherapeutic dose will, of course, be continuous rather than intermittentthroughout the dosage regimen.

Compounds of the present invention can also be administered in the formof liposome delivery systems, such as small unilamellar vesicles, largeunilamellar vesicles, multilamellar vesicles and the like. Liposomes canbe formed from a variety of phospholipids, such as cholesterol,stearylamine, phosphatidylcholines and the like.

The daily dose of a pharmaceutical composition of the present inventionmay be varied over a wide range from about 0.1 mg to about 5000 mg;preferably, the dose will be in the range of from about 1 mg to about100 mg per day for an average human. For oral administration, thecompositions are preferably provided in the form of tablets containing,0.01, 0.05, 0.1, 0.5, 1.0, 2.5, 5.0, 10.0, 15.0, 25.0, 50.0, 100, 150,200, 250 or 500 milligrams of the active ingredient for the symptomaticadjustment of the dosage to the subject to be treated. Advantageously, acompound of the present invention may be administered in a single dailydose or the total daily dosage may be administered in divided doses oftwo, three or four times daily.

It is also apparent to one skilled in the art that the therapeuticallyeffective dose for active compounds of the invention or a pharmaceuticalcomposition thereof will vary according to the desired effect.Therefore, optimal dosages to be administered may be readily determinedby those skilled in the art, and will vary with the particular compoundused, the mode of administration, the strength of the preparation, andthe advancement of the disease condition. In addition, factorsassociated with the particular subject being treated, including subjectage, weight, diet and time of administration, will result in the need toadjust the dose to an appropriate therapeutic level. The above dosagesare thus exemplary of the average case. There can, of course, beindividual instances where higher or lower dosage ranges are merited,and such are within the scope of this invention.

Compounds of this invention may be administered in any of the foregoingcompositions and dosage regimens or by means of those compositions anddosage regimens established in the art whenever use of the compounds ofthe invention as ERR-α inverse agonists is required for a subject inneed thereof.

2. Formulations

To prepare the pharmaceutical compositions of this invention, one ormore compounds of Formula (I) or salt thereof as the active ingredient,is intimately admixed with a pharmaceutical carrier according toconventional pharmaceutical compounding techniques, which carrier maytake a wide variety of forms depending of the form of preparationdesired for administration (e.g. oral or parenteral). Suitablepharmaceutically acceptable carriers are well known in the art.Descriptions of some of these pharmaceutically acceptable carriers maybe found in The Handbook of Pharmaceutical Excipients, published by theAmerican Pharmaceutical Association and the Pharmaceutical Society ofGreat Britain.

The compounds of the present invention may be formulated into variouspharmaceutical forms for administration purposes. Methods of formulatingpharmaceutical compositions have been described in numerous publicationssuch as Pharmaceutical Dosage Forms: Tablets, Second Edition, Revisedand Expanded, Volumes 1-3, edited by Lieberman et al; PharmaceuticalDosage Forms: Parenteral Medications, Volumes 1-2, edited by Avis et al;and Pharmaceutical Dosage Forms: Disperse Systems, Volumes 1-2, editedby Lieberman et al; published by Marcel Dekker, Inc.

3. Combination Therapy

The compounds of the present invention may be used in combination withone or more pharmaceutically active agents. These agents include ERR-αantagonists, glucokinase modulators, anti-diabetic agents, other lipidlowering agents, direct thrombin inhibitor (DTI), as well as lipidlowering agents such as statin drugs and the fibrates.

ERR-α antagonists include, for example, all the compounds disclosed inUS-2006-0014812-A1, particularly those of the formula

wherein:

-   -   n is 0 or 1;    -   Z is —O—, —S—, >NH, or >NR^(a) where R^(a) is alkyl, cycloalkyl,        phenyl, or heterocycloalkyl;    -   X is an aryl or heteroaryl group;    -   R³ is —H or —O-alkyl unsubstituted or substituted with one or        more substituents independently selected from the group        consisting of —OH, halo, —CN, —O-alkyl, and —N(R^(w))R^(x) where        R^(w) and R^(x) are each independently —H or alkyl;    -   R⁴ is selected from the group consisting of —H, halo, —O-alkyl,        —CN, —NO₂, and —COOH; and    -   R⁵ and R⁶ are each independently —CN; —COOH; or a moiety        selected from the group consisting of —COO-alkyl, —(C═O)alkyl,        —(S═(O)_(m))-aryl where m is 0, 1, or 2, cycloalkyl,        heterocycloalkyl, —(C═O)phenyl, heteroaryl, and        —(C═O)heterocycloalkyl; or R⁵ and R⁶ taken together with the        carbon to which they are attached form an optionally benzofused        heterocycloalkyl or cycloalkyl moiety;    -   wherein each such moiety is unsubstituted or substituted with        one or more substituents independently selected from the group        consisting of: —OH; ═O;═S; alkyl optionally substituted with        —OH, —O-alkyl, phenyl, —NH₂, —NH(alkyl), —N(alkyl)₂, halo, —CF₃,        —COOH, or —COO-alkyl; —O-alkyl; phenyl; —O— phenyl; benzyl;        —O-benzyl; cycloalkyl; —O-cycloalkyl; —CN; —NO₂; —N(R^(y))R^(z)        where R^(y) and R^(z) are each independently —H, alkyl, or        —(C═O)alkyl, or R^(y) and R^(z) taken together with the nitrogen        to which they are attached form a heterocycloalkyl wherein one        carbon ring atom is optionally replaced with >O, >NH or >N-alkyl        and where one carbon ring atom is optionally substituted with        —OH or ═O; —(C═O)N(R^(y))R^(z); —(N—R^(t))SO₂alkyl where R^(t)        is —H or alkyl; —(C═O)alkyl; —(S═(O)n)alkyl where n is 0, 1 or        2; —SO₂N(R^(y))R^(z) where R^(y) and R^(z) are as defined above;        —SCF₃; halo; —CF₃; —OCF₃; —COOH; and —COOalkyl;        or a pharmaceutically acceptable salt, pharmaceutically        acceptable prodrug, or pharmaceutically active metabolite of        such compound.

Anti-obesity agents can be classified into several categories based uponthe mechanism of action. These agents include selective serotoninreuptake inhibitors (SSRIs), serotonin agonists, serotonin andnorepinephrine reuptake inhibitors, pancreatic lipase inhibitors,β3-adrenoreceptor agonists, NPY antagonists, melanocortin receptoragonists, leptin-targeted agents, CB1 antagonists (e.g. Rimonabant),monoamine reuptake inhibotors (e.g. Sibutramine), and lipase inhibitor s(e.g. Orlistat).

Serotonin agonist agents such as dexfenfluramine and fenfluramine werereported to cause cardiac valvular abnormalities when used at theprescribed dosage in combination with phentermine. Selective serotoninreuptake inhibitors (SSRIs) are generally used for the treatment ofdepression. These agents include fluoxetine (Prozac), paroxetine,fluvoxamine and sertraline.

Representative serotonin modulators are listed below:

(A) Selective Serotonin Reuptake Inhibitors (SSRIs)

-   -   1. Citalopram (1-(3-(dimethylamino)        propyl)-1-(4-fluorophenyl)-1,3-dihydro-5-isobenzofurancarbo        nitrile, also known as citalopram hydrobromide (USAN),        nitalopram, nitalapram, ZD 211, LU 10171, Lu10-171, LU 10171-B,        CIPRAMIL, SEROPRAM, CIPRAM, ELOPRAM,

LUPRAM, SEPRAM, PRISDAL, or CELEXA);

-   -   2. Fluoxetine (benzenepropanamine,        N-Methyl-gamma-[4-(trifluoromethyl)phenoxy]-, (±) hydrochloride,        also known as LY 110140, RENEURON, SARAFEM, or PROZAC);    -   3. Fluvoxamine        (5-methoxy-1-(4-(trifluoromethyl)phenyl)-1-pentanone        (E)-O-(2-aminoethyl)oxime, also known as fluvoxamine maleate        (USAN), DU 23000, MK 264, SME 3110, FEVARIN, FLOXYFRAL, LUVOX,        DUMYROX, DUMIROX, FLAVOXYL, FAVERIN, or DEPROMEL);    -   4. Indeloxazine ((+, −)-2-((indel-7-yloxy)methyl)morpholine,        also known as ideloxazine, YM 08054, Cl 874, ELEN, or NOIN);    -   5. Paroxetine hydrochloride        ((3S,4R)-3-((1,3-benzodioxol-5-yloxy)methyl)-4-(4-fluorophenyl)piperidine        hydrochloride, or piperidine,        3-((1,3-benzodioxol-5-yloxy)methyl)-4-(4-fluorophenyl)-, (3S        -trans)-, also known as FR 7051, FG-7051, BRL 29060, BRL 29060A,        NNC 207051, SI 211103, CASBOL, SEROXAT, AROPAX, PAXIL, TAGONIS,        FROSINOR, DEROXAT, SEREUPIN, MOTIVAN, or PAXIL CR);    -   6. Sertraline (1-naphthalenamine,        4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-N-methyl-, (1S-cis)-        or        1-Naphthalenamine,4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-N-methyl-,        (1S -cis), also known as CP 51974, CP 51974 01, AREMIS,        BESITRAN, GLADEM, LUSTRAL, SERAD, SERLAIN, SERLIFT, TATIG, or        ZOLOFT);    -   7. Tianeptine (7-((3-chloro-6,11-dihydro-6-methyldibenzo (c, f)        (1,2) thiazepin-11-yl)amino)heptanoic acid S,S-dioxide, also        known as S 1574, or STABLON);    -   8. Centpropazine        (1-(p-propionylphenoxy)-3-(Nsup(4)-henylpiperazynyl)-propan-2-ol);    -   9. Paroxetine (GEOMATRIX drug delivery system)        (piperidine,3-((1,3-benzodioxol-5-yloxy)methyl)-4-(4-fluorophenyl)-,        (3S -trans)-, also known as paroxetine, GEOMATRIX, PAXIL CR);    -   10. Escitalopram        ((1S)-1-(3-(dimethylamino)propyl)-1-(4-fluorophenyl)-1,3-dihydro-5-isobenzofuran        carbonitrile, or        5-Isobenzofurancarbonitrile,1-(3-(dimethylamino)propyl)-1-(4-fluorophenyl)-1,3        -dihydro-, (S)—, also known as escitalopram, xalate (USAN),        citalopram, (S)(+)-citalopram, LU 26042, LU 26054, Lu26-054, or        CIPRALEX);    -   11. Litoxetine (4-[(2-Naphthalenyl)methoxy]piperidine, also        known as SL 810385);    -   12. (S)-Fluoxetine ((S)—N-methyl-gamma        -(4-(trifluoromethyl)phenoxy)benzenepropanamine);    -   13. Cericlamine ((+,        −)-3,4-dichloro-beta-(dimethylamino)-beta-methylbenzenepropanol,        also known as JO 1017(+, −), JO 1239(−), or JO 1240(+));    -   14. Dapoxetine        ((+)-(S)—N,N-dimethyl-alpha-(2-(1-naphthyl-oxy)ethyl)benzylamine        HCl, also known as LY-210448 or LY-243917);    -   15. 6-Nitroquipazine derivatives;    -   16. Series of substituted 6-nitroquipazines (Pharmaprojects        No.3391);    -   17. AAL 13 (2-(4-(3-chloropropyl)-1-piperazinyl)quinoline);    -   18. Depression therapy (by Vita Invest, Spain);    -   19. DUP 631 (C₁₃H₂₃NO₂S);    -   20. F 4503 (by Ferrer, Spain);    -   21. Series of indolylcyclohexylamines (Pharmaprojects No.6443,        American Home Products);    -   22. LY 280253        (N-Methyl-N-[3-[4-(methylthio)phenoxy)-3-phenylpropyl]amine);    -   23. LY 285974 (by Lilly);    -   24. Omiloxetine        (Ethanone,2-((3R,4S)-3-((1,3-benzodioxol-5-yloxy)methyl)-4-(4-fluorophenyl)-1-piperidinyl)-1-(4-fluorophenyl)-,        rel-, also known as FI-4500, FI-4501, FI-4503); and    -   25. WF 31        (8-Methyl-2beta-propanoyl-3beta-(4-(1-methylethyl)-phenyl)-8-azabicyclo[3.2.1]);

(B) Serotonin Agonists and Partial Agonists

-   -   1. Dexfenfluramine; and    -   2. Fenfluramine;

(C) Serotonin Reuptake Inhibitor with Serotonin Agonist Activity

-   -   1. EMD-68843 (2-benzofurancarboxamide,        5-(4-(4-(5-cyano-1H-indol-3-yl)butyl)-1-piperazinyl)-, also        known as SB-659746-A);    -   2. OPC-14523 (2(1H)-quinolinone,        1-(3-(4-(3-chlorophenyl)-1-piperazinyl)propyl)-3,4-dihydro-5-methoxy);    -   3. Vilazodone        (5-{4-[4-(5-Cyano-3-indolyl)-butyl]-1-piperazinyl}-benzofuran-2-carboxamide,        also known as EMD 68843 or SB 659746A);    -   4. Series of condensed thiazoles (3-(benzo (b)        thiophen-3-yl)-5,6-dihydroimidazo        (2,1-b)thiazolemonohydrobromide dihydrate, Pharmaprojects        No.5274, Abbott); and    -   5. VN-2222 (VN-8522, by Vita Invest, Spain).

Preferred examples of serotonin modulators include selective serotoninreuptake inhibitors such as Citalopram, Fluoxetine, Fluvoxamine,Indeloxazine, Paroxetine hydrochloride, Sertraline, Tianeptine,Centpropazine, Paroxetine, Escitalopram, and Litoxetine.

The following are also anti-obesity agents useful in the combinationtherapies of the present invention:

(A) Amylin and Amylin Analogs

-   -   1. Pramlintide        (I-Lysyl-I-cysteinyl-I-asparaginyl-I-threonyl-I-alanyl-I-threonyl-I-cysteinyl-I-alanyl-I-threonyl-I-glutaminyl-I-        arginyl-I-leucyl-I-alanyl-I-asparaginyl-I-phenylalanyl-I-leucyl-I-valyl-I-histidyl-I-seryl-I-seryl-I-asparaginyl-I-asparaginyl-I-        phenylalanylglycyl-I-prolyl-I-isoleucyl-I-leucyl-I-prolyl-I-prolyl-I-threonyl-I-asparaginyl-I-valylglycyl-I-seryl-I-asparaginyl-I-threonyl-I-        tyrosinamide cyclic (2-7)-disulfide, also known as pramlintide        acetate, AC 137, ACO 137, AC 0137, SYMLIN, Tripro-amylin, or        NORMYLIN);    -   2. Amylin agonists;    -   3. ACO 253 (AC 253, GG 747, GR 1150747A, or ANTAM);

(B) Ciliary Neurotrophic Factors (CNTF)

-   -   1. AXOKINE;    -   2. PEG-AXOKINE;    -   3. Peptide mimic of ciliary neurotrophic factor (CNTF mimic,        also known as MYELOS);    -   4. Ciliary neurotrophic factor (CNTF by Fidia, Italy);

(C) Glucagon-Like Peptide -1

-   -   1 AC-2993 (also known as exendin-4, AC-2993 LAR, Medisord        Exendin, AC-2993, Medisorb, or extendin-4, Amylin);    -   2. Exendin 4        (His-Gly-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Leu-Ser-Lys-Gln-Met-Glu-Glu-Glu-Ala-V-al-Arg-Leu-Phe-Ile-Glu-Trp-Leu-Lys-        Asn-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-amide, also        known as AC 2993, AC 2993 LAR, Medisord Exendin, or AC-2993,        Medisorb);    -   3. GLP-1 (Glucagon-like peptide-17-36 amide);    -   4. Glucagon-like peptide-1 oral transmucosal formulation;    -   5. Exendin 3        (His-Ser-Asp-Gly-Thr-Phe-Thr-Ser-Asp-Leu-Ser-Lys-Gln-Met-Glu-Glu-Glu-Ala-V-al-Arg-Leu-Phe-Ile-Glu-Trp-Leu-Lys-Asn-        Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-amide);

(D) Leptin & Leptin Mimetics

-   -   1. Leptin (2nd-generation);    -   2. Leptin agonists;    -   3. Leptin expression modulators;    -   4. Leptin signalling pathway modulators;    -   5. Leptin modulator;    -   6. Leptin (by IC Innovations, UK);    -   7. Leptin receptor, Monoclonal antibodies;    -   8. Recombinant native leptin;    -   9. LY-355101;    -   10. Leptin, Amylin

(E) Melanocortin Receptor Agonist (MC4)

-   -   1. HP-228 (Glycinamide,        N-acetyl-L-norleucyl-L-glutaminyl-L-histidyl-D-phenylalanyl-L-arginyl-D-tryptophyl-);    -   2. Melanocortin-4 receptor agonist (by Palatin, USA);    -   3. Melanocortin 4 agonist (by Pharmacopeia, Roche);    -   4. MC-4 agonists (by Millennium, Chiron)    -   5. Melanocortin-4 agonist (by Melacure Therapeutics, Sweden);    -   6. Melanocortin receptor modulators (Pharmaprojects No.5224,        Neurocrine Biosciences, US);    -   7. Pharmaprojects No.5967, Trega/Novartis;

(F) NPY Antagonists

-   -   1. AXC 0216;    -   2. AXC 1829;    -   3. SA-0204 (Neuropeptide Y antagonist, Apoptosis stimulator,        Lipid metabolism modulator);    -   4. Alpha-trinositol (D-myo-Inositol, 1,2,6-tris (dihydrogen        phosphate), also known as PP-56);    -   5. H 40922 (H 409/22);    -   6. BMS-192548 (1,11        (4H,5H)-naphthacenedione,2-acetyl-4a,12a-dihydro-3,4a,10,12,12a-pentahydroxy-8-methoxy-,        TAN 1612 isomer);    -   7. Alanex        (1,4-bis{(4-amino-6-methoxyphenylamino-1,2-dihydro-1,3,5-triazin-2-yl)-4-phenoxymethyl}benzene,        Neuropeptide Y derivatives);    -   8. PD-160170        (6-(2-isopropyl-benzenesulfonyl)-5-nitro-quinolin-8-ylamine);    -   9. 2,4-Diaminopyridine derivatives        (6-(5-ethyl-1,3,4-thiadiazol-2-ylthiomethyl)-4-morpholino-2-(3-(2-propenyloxycarbonylamino)benzylamino)pyridine,        Pharmaprojects No.5618, Banyu/Merck);    -   10. Arpromidine analogs;    -   11. Neuropeptide Y antagonist (Pharmaprojects No.4990, Pfizer);    -   12. 4 Methyl substituted benzimidazoles (NPY-1 antagonist, NPY-2        antagonist);    -   13. LY-366337 (Neuropeptide Y1 antagonist);    -   14. S-2501, S-25579, S-25584, S-25585, S-19528, S-34354 (all        Neuropeptide Y1/5 antagonists);    -   15. Neuropeptide Y antagonist (subtypes 1 and 5) and Galanin        receptor antagonist (Pharmaprojects No.4897, Bristol-Myers        Squibb);    -   16. Benzylamine derivatives        (1-arylpiperazinyl-1-alkyloxyphenyl-4-alkylcycloalkanes);    -   17. J-104870 (Neuropeptide Y1 antagonist, Appetite suppressant);    -   18. LY-357897 (Neuropeptide Y1 antagonist);    -   19. Neuropeptide Y1 antagonist (Pfizer/Neurogen);    -   20. SR-1 20107A (Neuropeptide Y1 antagonist);    -   21. BIBO-3304        ((R)—N-((4-(aminocarbonylaminomethyl)-phenyl)methyl)-N2-(diphenylacetyl)-argininamide        trifluoroacetate);    -   22. BIBP 3226        ((R)—N-(4-((aminoiminomethyl)amino)-1-((((4-hydroxyphenyl)methyl)amino)carbonyl)butyl)-alpha-phenylbenzeneacetamide,        or benzeneacetamide,        N-((1R)-4-((aminoiminomethyl)amino)-1-((((4-hydroxyphenyl)methyl)amino)carbonyl)butyl)-alpha-phenyl-);    -   23. SR 120819A (benzenepropanamide,        N-(1-((4-((((4-((dimethylamino)methyl)cyclohexy)methyl)amino)iminomethyl)phenyl)methyl)-2-oxo-2-(1-pyrrolidinyl)ethyl)-alpha-((2-naphthalenylsulfonyl)amino)-,        (alphaR—(N(R*(cis)), alphaR*))-);    -   24. NGD-95-1 (CP-422935, NGD 951);    -   25. Compounds with benzazepine nuclei (Neuropeptide Y1        antagonist);    -   26. Neuropeptide Y1 antagonist (by Yamanouchi Pharmaceutical);    -   27. GI-264879A (Neuropeptide Y1 antagonist);    -   28. GW-1229 ([2′,4],[2,4′]homodimer of        Ile-Glu-Pro-Dpr-Tyr-Arg-Leu-Arg-Tyr-CONH2, where Dpr is        diaminopropionic acid, also known as 1229U91, MN-24, GR-231118);    -   29. BIIE-0246 (Cyclopentaneacetamide,        N-[(1S)-4-[(aminoiminomethyl)amino]-1-[[[2-(3,5-dioxo-1,2-diphenyl-1,2,4-triazolidin-4-yl)ethyl]amino]carbonyl]butyl]-1-[2-[4-(6,11-dihydro-6-oxo-5H-dibenz[b,e]azepin-11-yl)-1-piperazinyl]-2-oxoethyl]-);    -   30. Neuropeptide Y2 antagonist (by Neurogen, USA);    -   31. Amide derivatives (Neuropeptide Y5 antagonist);    -   32. Neuropeptide Y agonist and antagonist-subtypes 1 and 5        (Schering-Plough)    -   33.        N-(sulfonamido)alkyl-[3a,4,5,9b-tetrahydro-1H-benzo[e]indol-2-yl]amine        (RWJPRI);    -   34. Neuropeptide Y5 antagonist (by Novartis);    -   35. Neuropeptide Y5 antagonist (by Pfizer/Neurogen);    -   36. Pyrrolo[3,2-d]pyrimidine based neuropeptide Y5 antagonists;    -   37. CGP-71683 (Pharmaprojects No. 5651, CGP-71683A);    -   38. Neuropeptide Y5 agonist/antagonist (Pharmaprojects No.5664,        Bayer);

(G) Histamine H3 Receptor Antagonists

-   -   1. GT-2331 (3-((1        R,2R)-2-(5,5-dimethyl-1-hexynyl)cyclopropyl)-1H-imidazole, also        known as PERCEPTIN);    -   2. Ciproxifan        (Cyclopropyl-(4-(3-1H-imidazol-4-yl)propyloxy)phenyl)methanone,        also known as BP 2359 or Compound 359);    -   3. Compound 421 (imidazoylpropanol derivative, INSERM        (France)/Bioprojet);    -   4. FUB 181 (3-(4-chlorophenyl)propyl-3-(1 H-imidazol-4-yl)propyl        ether);    -   5. GR 175737        (3-((4-chlorophenyl)methyl)-5-(2-(1H-imidazol-4-yl)ethyl)-1,2-oxadiazole);    -   6. GT 2227 (4-(6-cyclohexyl-3 (Z)-hexenyl)imidazole maleate);    -   7. GT 2394 ((1R,        2R)-(trans-2-Imidazol-4-ylcyclopropyl)-(cyclohexylmethoxy)carboxamide);    -   8. GT-2016 (piperidine,        1-(5-cyclohexyl-1-oxopentyl)-4-(1H-imidazol-4-yl)-);    -   9. Imoproxifan        (1-(4-(3-(1H-imidazol-4-yl)propoxy)phenyl)ethan-1-one oxime);    -   10. Impentamine (by Berlin Free University);    -   11. Abbott Laboratories H3 antagonist for Attention deficit        Hyperactivity Disorder (ADHD);    -   12. Gliatech (USA) H3 antagonist for eating disorder;    -   13. Series of novel carbamates as derivatives of        3-(1H-imidazol-4-yl)propanol with an N-alkyl chain;    -   14. Series of analogs with a neutral linker leading to        4-(1H-imidazol-4-ylmethyl)benzene;    -   15. Urea,        N-4-(1H-imidazol-4-ylmethyl)phenylmethyl-N′-(3,5-dichlorophenyl)-,        monohydrochloride;    -   16. Sch-50971 (1 H-imidazole,        4-[(3R,4R)-4-methyl-3-pyrrolidinyl]-);    -   17. Thioperamide        (N-cyclohexyl-4-(1H-imidazol-4-yl)-1-piperidinecarbothioamide,        also known as MR 12842);    -   18. UCL-1283 (by University College London);    -   19. UCL-1390 (4-(3-(1H-imidazol-4-yl)propoxy)benzonitrile);    -   20. UCL-1409 ((phenoxyalkyl)imidazoles);    -   21. UCL-1972 (by University College London);    -   22. Verongamine (benzenepropanamide,        3-bromo-.alpha.-(hydroxyimino)-N-[2-(1H-imidazol-4-yl)ethyl]-4-methoxy-,        (E)-);    -   23. VUF-9153 (Carbamimidothioic acid, [(4-chlorophenyl)methyl]-,        3-(1H-imidazol-4-yl)propyl ester, also known as Clobenpropit);

(H) Pancreatic Lipase Inhibitors

-   -   1. Orlistat (L-Leucine, N-formyl-,        1-((3-hexyl-4-oxo-2-oxetanyl)methyl)dodecyl ester, (2S-(2alpha        (R*),3beta))-, or N-formyl-L-leucine (2S-(2alpha        (R*),3beta))-1-((3-hexyl-4-oxo-2-oxetanyl)methyl)dodecyl ester,        also known as Orlipastat, RO 180647, Tetrahydrolipstatin (THL),        XENICAL, or ZENICAL);    -   2. ATL 962 (also known as AZM 119 or Alizyme);    -   3. GelTex (Anti-obesity therapeutics);    -   4. AZM-131 (by Yakurigaku Chuo Kenkyusho/Institute of Food        Research);    -   5. RED 103004 (XiMed Group (United Kingdom)/BioClin);

(I) Alpha Melanocyte Stimulating Hormone Analogues

-   -   1. Melanotan II        (acetyl-norleucyl-aspartyl-histidyl-D-phenylalanyl-arginyl-tryptophyl-lysinamide        C-4.2-N-6.7-lactam, also known as MT II);    -   2. MBU-23, MBU-23, MBU-24, MBU-27, MBU-28 and MBU-29 (all        described in WO 009827113);    -   3. MSH fusion toxin (also known as DAB389MSH, antimelanoma,        chimaera)    -   4. SHU-9119 (L-Lysinamide,        N-acetyl-L-norleucyl-L-.alpha.-aspartyl-L-histidyl-3-(2-naphthalenyl)-D-alanyl-L-arginyl-L-tryptophyl-,        (2.fwdarw.7)-lactam, also known as MBX 36)    -   5. SHU-9005 (a substituted derivative of alpha-MSH)    -   6. ZYC-200 (alpha-MSH, Schepens/ZYCOS with BIOTOPE expression        cassette system)

(J) Mixed Serotonin Reuptake Unhibitor with Serotonin or AlphaAdrenergic Antagonist Activity

-   -   1. Nefazodone        (2-(3-(4-(3-chlorophenyl)-1-piperazinyl)propyl)-5-ethyl-2,4-dihydro-4-(        2-phenoxyethyl)-3H-1,2,4-triazol-3-one, also known as MJ 13754,        MS 13754, BMY 13754, BMY 137541, SERZONE, DUTONIN, RESERIL,        NEFADAR, NIFEREL, MENFAZONA, RULIVAN, DEPREFAX, or SERZONIL);    -   2. YM 992 ((S)-2-(((7-fluoro-2,3-dihydro-1        H-inden-4-yl)oxy)methyl)morpholine hydrochloride, or        (S)-2-(((7-fluoro-2,3-dihydro-1H-inden-4-yl)oxy)methyl)morpholine        hydrochloride, also known as YM 35992);    -   3. A 80426        ((R)—N-methyl-N-((1,2,3,4-tetrahydro-5-methoxy-1-aphthalenyl)methyl)-6-benzofuranethanamine);    -   4. 5-HT1A antagonist (by Vita-invest, Spain);    -   5. Nefazodone metabolite (by Sepracor, USA);    -   6. Serotonin reuptake inhibitors/serotonin 1A antagonists        (Wyeth-Ayerst)

(K) Appetite-Suppressants Acting Through Adrenergic Mechanisms

-   -   1. benzphetamine;    -   2. phenmetrazine;    -   3. phentermine;    -   4. diethylpropion;    -   5. mazindol;    -   6. sibutramine;    -   7. phenylpropanolamine;    -   8. ephedrine

(L) Mixed Serotonin & Dopamine Reuptake Inhibitors

-   -   1. BL-1834 (1-propanamine, 3-dibenz (b, e) oxepin-11        (6H)-ylidene-N, N-dimethyl);    -   2. NS-2389 or NS-2347 (GW-650250A, GW 650250);    -   3. (R)-Sibutramine;    -   4. NS-2359 (by NeuroSearch, Denmark);    -   5. RTI-112 or RTI-113 or RTI-177 (8-Azabicyclo (3.2.1)        octane-2-carboxylic acid, 3-(4-chloro-3-methylphenyl)-8-methyl-,        methyl ester, hydrochloride, (1R,2S,3S,5S));    -   6. BSF-74681 (Abbott);    -   7. Hyperforin trimethoxybenzoate (IDN-5491);

(M) Mixed Serotonin Reuptake Inhibitors and Dopamine Antagonist

-   -   1. SLV-310 (Solvay, Belgium);    -   2. EMD 86006        (3-(2-(3-(4-fluorophenyl)benzylamino)ethoxy)benzonitrile);    -   3. SLV 301 (by Solvay);

(N) Norepinephrine & Serotonin Reuptake Inhibitors (NSRI)

-   -   1. Milnacipran (Cyclopropanecarboxamide,        2-(aminomethyl)-N,N-diethyl-1-phenyl-, cis-(+, −)-, or        (±)-cis-2-(Aminomethyl)-N-diethyl-1-phenyl cyclopropane        carboxamide hydrochloride, also known as F-2207, F-2641, TN-912,        DALCIPRAN, IXEL, MIDACIPRAN, MIDALCIPRAN, MILNACIPRAN SR,        TOLEDOMIN);    -   2. Tramadol, Purdue (cyclohexanol,        2-((dimethylamino)methyl)-1-(3-methoxyphenyl)-, cis-(+/−), also        known as TRAMADOL, Tramadol, CR, or Toray);    -   3. Milnacipran (drug delivery system, sustained release);    -   4. Duloxetine        ((S)-N-methyl-gamma-(1-naphthalenyloxy)-2-thiophenepropanamine,        or        (+)-(S)—N-Methyl-gamma-(1-naphthyloxy)-2-thiophene-propylamine        hydrochloride, also known as LY 248686, duloxetine oxalate,        LY-223332, LY-223743, LY-223994, LY-227750, LY-227942,        LY-228993, LY-248686, LY-264452, LY-264453, LY-267826″    -   5. Naltrexone+tramadol        (morphinan-6-one,17-(cyclopropylmethyl)-4,5-epoxy-3,14-dihydroxy-,        (5alpha)-, mixt withcyclohexanol,        2-((dimethylamino)methyl)-1-(3-methoxyphenyl)-, cis-(+/−)-, also        known as PTI-601, tramadol +naltrexone, Pain T)    -   6. (S) sibutramine        ((S)-1-(4-chlorophenyl)-N,N-dimethyl-alpha-(2-methylpropyl)cyclobutanemethanamine);    -   7. Tramadol, Labopharm (cyclohexanol,        2-((dimethylamino)methyl)-1-(3-methoxyphenyl)-, cis-(+/−), also        known as tramadol, Contramid);    -   8. F 98214TA (by FAES, Spain);    -   9. S 33005        ((−)-1-(1-Dimethylaminomethyl-5-methoxybenzocyclobutan-1-yl)cyclopentanol);    -   10. Tacrine analogues, SIDR;

(O) Serotonin, Norepinephrine and Dopamine Reuptake Inhibitors

-   -   1. Sibutramine        (cyclobutanemethanamine,1-(4-chlorophenyl)-N,N-dimethyl-alpha-(2-methylpropyl)-,        or        1-(4-chlorophenyl)-N,N-dimethyl-alpha-(2-methylpropyl)cyclobutanemetha        namine hydrochloride monohydrate, also known as Sibutramine        hydrochloride monohydrate, BTS-54354, BTS-54505, BTS-54524,        KES-524, MERIDIA, REDUCTIL, RADUCTIL, REDUCTASE, PLENTY,        ECTIVA);    -   2. Venlafaxine        (cyclohexanol,1-[2-(dimethylamino)-1-(4-methoxyphenyl)ethyl],        also known as WY 45030, WY 45651, WY 45655, DOBUPAL, EFECTIN,        EFEXOR, EFFEXOR, ELAFAX, VANDRAL, TREVILOR);    -   3. Venlafaxine XR (cyclohexanol,        1-(2-(dimethylamino)-1-(4-methoxyphenyl)ethyl)-, hydrochloride,        also known as EFFEXOR XR,l EFFEXOR ER, EFFEXOR XL, EFFEXOR LP,        DOBUPAL RETARD, VANDRAL RETARD, EFFEXOR-EXEL 75, EFEXOR XR,        EFEXOR DEPOT, ELAFAX XR);    -   4. Venlafaxine (drug delivery system, OROS oral controlled        release, also known as venlafaxine, OROS, or EFEXOR XR)    -   5. (+)-Desmethylsibutramine (also known as DDMS,        Didesmethylsibutramine-Sepracor);    -   6. BTS-74398        (1-[1-(3,4-Dichlorophenyl)cyclobutyl]-2-(3-dimethylaminopropylthio)ethanone,        Abbott Pharmaprojects No. 6247);    -   7. Desmethylvenlafaxine (by Sepracor);

(P) Appetite-Suppressant Agents Acting through Dopamine Mechanisms

-   -   1. Apomorphine;

(Q) Selective Norepinephrine (Noradrenaline) Reuptake Inhibitors

-   -   1. Reboxetine        ((2S)-rel-2-((R)-(2-ethoxyphenoxy)phenylmethyl)morpholine, or        morpholine, 2-[(2-ethoxyphenoxy)phenylmethyl]-, (R,S)-,        methanesulfonate, also known as reboxetine mesylate (USAN), FCE        20124, FCE 21684, PNU 155950E, EDRONAX, PROLIFT, VESTRA, IRENON,        NOREBOX);    -   2. Tomoxetine ((gamma.R)-N-methyl-gamma-(2-methylphenoxy)        benzenepropanamine, or        (−)-N-Methyl-3-phenyl-3-(o-tolyloxy)-propylamine hydrochloride,        also known as LY 139603, LY 135252, LY 139602);    -   3. Hydroxynortriptyline ((E)-10-11-dihydro-5-(3-(methylamino)        propylidene)-5H-dibenzo-(a, d) cyclohepten-10-ol);    -   4. LY 368975        ((R)-N-Methyl-3-[2-(methylsulfanyl)phenoxy]-3-phenyl-propylamine        hydrochloroide);

(R) Combined Norepinephrine and Dopamine Reuptake Inhibitors

-   -   1. Bupropion        (1-(3-chlorophenyl)-2-((1,1-dimethylethyl)amino)-1-propanone,        also known as bupropion hydrochloride (USAN), bupropin,        amfebutamone, BW 323U, WELLBUTRIN, QUOMEM, or ZYBAN);    -   2. GW 320659        ((2S-(2alpha,3alpha,5alpha))-2-(3,5-difluorophenyl)-3,5-dimethyl-2-morpholinol        hydrochloride, also known as 1555, 1555U88, BW 1555U88);    -   3. Hydroxy bupropion (also known as bupropion, R—, or        R-bupropion);    -   4. (−) Didesmethylsibutramine (also known as        (S)-didesmethylsibutramine, desmethylsibutramine, (−)-DDMS or        MERIDIA (urogenital));

(S) Mixed Norepinephrine Reuptake Inhibitor and Other NeurotransmitterAntagonists

-   -   1. Zotepine (2-((8-chlorodibenzo (b,        f)thiepin-10-yl)oxy)-N,N-dimethylethylamine, also known as        LODOPIN, NIPOLEPT, ZOLEPTIL, ZOPITE, SETOUS, MAJORPIN);    -   2. MCI 225        (4-(2-fluorophenyl)-2-methyl-6-(piperazin-1-yl)-3a,7a-dihydrothieno        (2,3-d) pyrimidine, or        4-(2-Fluorophenyl)-6-methyl-2-piperazinothieno [2,3-d]pyrimidine        hydrochloride hydrate);    -   3. A 75200 ((R*,        R*)-(+,−)-3-phenyl-1-((6,7,8,9-tetrahydronaphtho        (1,2-d)-1,3-dioxol-6-yl)methyl)pyrrolidine);

(T) Combined Serotonin Reuptake Inhibitors and Sigma ReceptorAntagonists

-   -   1. E-5296 (by Esteve, Spain);    -   2. E-6276 (by Esteve, Spain);    -   3. E-5842 (pyridine,        4-(4-fluorophenyl)-1,2,3,6-tetrahydro-1-(4-(1H-1,2,4-triazol-1-yl)butyl)-,        2-hydroxy-1,2,3-propanetricarboxylate (1:1));    -   4. E 5826 (citrate salt of E-5842);

(U) Other Neurotransmitter Modulators with Serotonin or NorepinephrineUptake Inhibitor Activity

-   -   1. Pirlindole (1H-pyrazino (3,2,1-jk) carbazole,        2,3,3a,4,5,6-hexahydro-8-methyl-, also known as CAS-125,        Pyrazidol, pirazidol, LIFRIL, IMPLEMENTOR);    -   2. NS-2330 (by NeuroSearch, Denmark);    -   3. VAN-H36 (by Vita-invest, Spain);    -   4. UR 1827        (2-(1-Benzylpiperidin-4-yl)-1-[4-(5-methylpyrimidin-4-ylamino)phenyl]-1-ethanone);

(V) C-75 (Fatty Acid Synthase Inhibitor)

(W) S 15261 (L-4-(2-(2-(9-Fluorenyl)acetamido)ethyl)benzoic acid2-(2-methoxy-2-(3-(trifluoromethyl)phenyl)ethylamino)ethyl ester)

(X) S 100B (Neurotrophic Factor)

(Y) Stimulators of Uncoupling Protein Function

(Z) Cholecystokinin Agonists

(AA) Androgens

-   -   1. dehydroepiandrosterone;    -   2. dehydroepiandrosterone derivatives (such as etiocholandione);

(BB) Testosterone

(CC) Anabolic Steroids (eg, Oxandrolone)

(DD) Steroidal Hormones

(EE) Amylase Inhibitors

(FF) Enterostatin Agonists/Mimetics

(GG) Orexin/Hypocretin Antagonists

(HH) Urocortin Antagonists

(II) Bombesin Agonists

(JJ) Modulators of Protein Kinase A

(KK) Corticotropin-Releasing Factor Mimetics

(LL)Cocaine-and Amphetamine-Regulated Transcript Mimetics

(MM) Calcitonin-Gene Related Peptide Mimetics

(NN) Nizatidine (Axid)

Other agents useful for the combination therapy of the present inventioninclude glucokinase modulators include:

Anti-diabetic agents include RXR modulators such as:

-   -   (1) bexarotene        (4-(1-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthalenyl)ethenyl)benzoic        acid, known as TARGRETIN, TARGRETYN, TARGREXIN; also known as        LGD 1069, LG 100069, LG 1069, LDG 1069, LG 69, RO 264455);    -   (2) 9-cis-retinoic acid;    -   (3) AGN-4326 (also known as ALRT-4204, AGN-4204, ALRT-326,        ALRT-324, or LGD 1324);    -   (4) LGD 1324 (ALRT 324);    -   (5) LG 100754;    -   (6) LY-510929;    -   (7) LGD 1268        (6-(1,1,4,4,6-pentamethyl-1,2,3,4-tetrahydro-naphth-7-ylcycloprop-1-yl)nicotinic        acid, known as ALRT 268 or LG 100268); and    -   (8) LG 100264.

Anti-diabetic agents also include thiazolidinedione andnon-thiazolidinedione insulin sensitizers, which decrease peripheralinsulin resistance by enhancing the effects of insulin at target organsand tissues.

The following agents are known to bind and activate the nuclear receptorperoxisome proliferator-activated receptor-gamma (PPARγ) which increasestranscription of specific insulin-responsive genes. Examples ofPPAR-gamma agonists are thiazolidinediones such as:

-   -   (1) rosiglitazone        (2,4-thiazolidinedione,5-((4-(2-(methyl-2-pyridinylamino)ethoxy)phenyl)methyl)-,        (Z)-2-butenedioate (1:1) or        5-((4-(2-(methyl-2-pyridinylamino)ethoxy)phenyl)methyl)-2,4-thiazolidinedione,        known as AVANDIA; also known as BRL 49653, BRL 49653C, BRL        49653c, SB 210232, or rosiglitazone maleate);    -   (2) pioglitazone (2,4-thiazolidinedione,        5-((4-(2-(5-ethyl-2-pyridinyl)ethoxy)phenyl)methyl)-,        monohydrochloride, (+−)-or        5-((4-(2-(5-ethyl-2-pyridyl)ethoxy)phenyl)methy)-2,4-thiazolidinedione,        known as ACTOS, ZACTOS, or GLUSTIN; also known as AD 4833, U        72107, U 72107A, U 72107E, pioglitazone hydrochloride (USAN));    -   (3) troglitazone        (5-((4-((3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-1-benzopyran-2-yl)methoxy)phenyl)methyl)-2,4-thiazolidinedione,        known as NOSCAL, REZULIN, ROMOZIN, or PRELAY; also known as Cl        991, CS 045, GR 92132, GR 92132X);    -   (4) isaglitazone        ((+)-5-[[6-[(2-fluorophenyl)methoxy]-2-naphthalenyl]methyl]-2,4-thiazolidinedione        or        5-((6-((2-fluorophenyl)methoxy)-2-naphthalenyl)methyl-2,4-thiazolidinedione        or        5-(6-(2-fluorobenzyloxy)naphthalen-2-ylmethyl)thiazolidine-2,4-dione,        also known as MCC-555 or neoglitazone); and    -   (5) 5-BTZD.

Additionally, the non-thiazolidinediones that act as insulin sensitizingagents include, but are not limited to:

-   -   (1) JT-501 (JTT 501, PNU-1827, PNU-716-MET-0096, or PNU 182716:        isoxazolidine-3, 5-dione,        4-((4-(2-phenyl-5-methyl)-1,3-oxazolyl)ethylphenyl-4)methyl-);    -   (2) KRP-297        (5-(2,4-dioxothiazolidin-5-ylmethyl)-2-methoxy-N-(4-(trifluoromethyl)benzyl)benzamide        or        5-((2,4-dioxo-5-thiazolidinyl)methyl)-2-methoxy-N-((4-(trifluoromethyl)phenyl)methyl)benzamide);        and    -   (3) Farglitazar (L-tyrosine,        N-(2-benzoylphenyl)-o-(2-(5-methyl-2-phenyl-4-oxazolyl)ethyl)-or        N-(2-benzoylphenyl)-O-(2-(5-methyl-2-phenyl-4-oxazolyl)ethyl)-L-tyrosine,        or GW2570 or GI-262570).

Other anti-diabetic agents have also been shown to have PPAR modulatoractivity such as PPAR gamma, SPPAR gamma, and/or PPAR delta/gammaagonist activity. Examples are listed below:

-   -   (1) AD 5075;    -   (2) R 119702 ((+−)-5-(4-(5-Methoxy-1        H-benzimidazol-2-ylmethoxy)benzyl)thiazolin-2,4-dione        hydrochloride, or Cl 1037 or CS 011);    -   (3) CLX-0940 (peroxisome proliferator-activated receptor alpha        agonist/peroxisome proliferator-activated receptor gamma        agonist);    -   (4) LR-90 (2,5,5-tris (4-chlorophenyl)-1,3-dioxane-2-carboxylic        acid, PPARdelta/γ agonist);    -   (5) Tularik (PPARγ agonist);    -   (6) CLX-0921 (PPARγ agonist);    -   (7) CGP-52608 (PPAR agonist);    -   (8) GW-409890 (PPAR agonist);    -   (9) GW-7845 (PPAR agonist);    -   (10) L-764406 (PPAR agonist);    -   (11) LG-101280 (PPAR agonist);    -   (12) LM-4156 (PPAR agonist);    -   (13) Risarestat (CT-112);    -   (14) YM 440 (PPAR agonist);    -   (15) AR-H049020 (PPAR agonist);    -   (16) GW 0072        (4-(4-((2S,5S)-5-(2-(bis(phenylmethyl)amino)-2-oxoethyl)-2-heptyl-4-oxo-3-thiazo        lidinyl)butyl)benzoic acid);    -   (17) GW 409544 (GW-544 or GW-409544);    -   (18) NN 2344 (DRF 2593);    -   (19) NN 622 (DRF 2725);    -   (20) AR-H039242 (AZ-242);    -   (21) GW 9820 (fibrate);    -   (22) GW 1929        (N-(2-benzoylphenyl)-O-(2-(methyl-2-pyridinylamino)ethyl)-L-tyrosine,        known as GW 2331, PPAR alpha/y agonist);    -   (23) SB 219994        ((S)-4-(2-(2-benzoxazolylmethylamino)ethoxy)-alpha-(2,2,2-trifluoroethoxy)benzen        epropanoic acid or        3-(4-(2-(N-(2-benzoxazolyl)-N-methylamino)ethoxy)phenyl)-2(S)-(2,2,2-trifluoroethoxy)propionic        acid or benzenepropanoic acid,        4-(2-(2-benzoxazolylmethylamino)ethoxy)-alpha-(2,2,2-trifluoroethoxy)-,        (alphaS)-, PPARalpha/γ agonist);    -   (24) L-796449 (PPAR alpha/γ agonist);    -   (25) Fenofibrate (Propanoic acid,        2-[4-(4-chlorobenzoyl)phenoxy]-2-methyl-, 1-methylethyl ester,        known as TRICOR, LIPCOR, LIPANTIL, LIPIDIL MICRO PPAR alpha        agonist);    -   (26) GW-9578 (PPAR alpha agonist);    -   (27) GW-2433 (PPAR alpha/γ agonist);    -   (28) GW-0207 (PPARγ agonist);    -   (29) LG-1 00641 (PPARγ agonist);    -   (30) LY-300512 (PPARγ agonist);    -   (31) NID525-209 (NID-525);    -   (32) VDO-52 (VDO-52);    -   (33) LG 100754 (peroxisome proliferator-activated receptor        agonist);    -   (34) LY-510929 (peroxisome proliferator-activated receptor        agonist);    -   (35)bexarotene        (4-(1-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthalenyl)ethenyl)benzoic        acid, known as TARGRETIN, TARGRETYN, TARGREXIN; also known as        LGD 1069, LG 100069, LG 1069, LDG 1069, LG 69, RO 264455); and    -   (36) GW-1536 (PPAR alpha/γ agonist).

Other insulin sensitizing agents include, but are not limited to:

-   -   (1) INS-1 (D-chiro inositol or        D-1,2,3,4,5,6-hexahydroxycyclohexane);    -   (2) protein tyrosine phosphatase 1 B (PTP-1B) inhibitors;    -   (3) glycogen synthase kinase-3 (GSK3) inhibitors;    -   (4)beta 3 adrenoceptor agonists such as ZD 2079        ((R)—N-(2-(4-(carboxymethyl)phenoxy)ethyl)-N-(2-hydroxy-2-phenethyl)ammonium        chloride, also known as ICI D 2079) or AZ 40140;    -   (5) glycogen phosphorylase inhibitors;    -   (6) fructose-1,6-bisphosphatase inhibitors;    -   (7) chromic picolinate, vanadyl sulfate (vanadium oxysulfate);    -   (8) KP 102 (organo-vanadium compound);    -   (9) chromic polynicotinate;    -   (10) potassium channel agonist NN 414;    -   (11) YM 268 (5,5′-methylene-bis (1,4-phenylene)bismethylenebis        (thiazolidine-2,4-dione);    -   (12) TS 971;    -   (13) T 174        ((+−)-5-(2,4-dioxothiazolidin-5-ylmethyl)-2-(2-naphthylmethyl)benzoxazole);    -   (14) SDZ PGU 693 ((+)-trans-2        (S-((4-chlorophenoxy)methyl)-7alpha-(3,4-dichlorophenyl)tetrahydropyrrolo        (2,1-b) oxazol-5 (6H)-one);    -   (15) S 15261        ((−)-4-(2-((9H-fluoren-9-ylacetyl)amino)ethyl)benzoic acid        2-((2-methoxy-2-(3-(trifluoromethyl)phenyl)ethyl)amino)ethyl        ester);    -   (16) AZM 134 (Alizyme);    -   (17) ARIAD;    -   (18) R 102380;    -   (19) PNU 140975 (1-(hydrazinoiminomethyl)hydrazino)acetic acid;    -   (20) PNU 106817 (2-(hydrazinoiminomethyl)hydrazino)acetic acid;    -   (21) NC 2100        (5-((7-(phenylmethoxy)-3-quinolinyl)methyl)-2,4-thiazolidinedione;    -   (22) MXC 3255;    -   (23) MBX 102;    -   (24) ALT 4037;    -   (25) AM 454;    -   (26) JTP 20993        (2-(4-(2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy)benzyl)-malonic        acid dimethyl dieester);    -   (27) Dexlipotam (5 (R)-(1,2-dithiolan-3-yl)pentanoic acid, also        known as (R)-alpha lipoic acid or (R)-thioctic acid);    -   (28) BM 170744 (2,2-Dichloro-12-(p-chlorophenyl)dodecanoic        acid);    -   (29) BM 152054        (5-(4-(2-(5-methyl-2-(2-thienyl)oxazol-4-yl)ethoxy)benzothien-7-ylmethyl)thiazolidine-2,        4-dione);    -   (30) BM 131258        (5-(4-(2-(5-methyl-2-phenyloxazol-4-yl)ethoxy)benzothien-7-ylmethyl)thiazolidine-2,        4-dione);    -   (31) CRE 16336 (EML 16336);    -   (32) HQL 975        (3-(4-(2-(5-methyl-2-phenyloxazol-4-yl)ethoxy)phenyl)-2        (S)-(propylamino)propionic acid);    -   (33) DRF 2189        (5-((4-(2-(1-Indolyl)ethoxy)phenyl)methyl)thiazolidine-2,4-dione);    -   (34) DRF 554158;    -   (35) DRF-NPCC;    -   (36) CLX 0100, CLX 0101, CLX 0900, or CLX 0901;    -   (37) IkappaB Kinase (IKK B) Inhibitors    -   (38) mitogen-activated protein kinase (MAPK) inhibitors    -   p38 MAPK Stimulators    -   (39)phosphatidyl-inositide triphosphate    -   (40) insulin recycling receptor inhibitors    -   (41) glucose transporter 4 modulators    -   (42) TNF-α antagonists    -   (43) plasma cell differentiation antigen-1 (PC-1) Antagonists    -   (44) adipocyte lipid-binding protein (ALBP/aP2) inhibitors    -   (45)phosphoglycans    -   (46) Galparan;    -   (47) Receptron;    -   (48) islet cell maturation factor;    -   (49) insulin potentiating factor (IPF or insulin potentiating        factor-1);    -   (50) somatomedin C coupled with binding protein (also known as        IGF-BP3, IGF-BP3, SomatoKine);    -   (51) Diab II (known as V-411) or Glucanin, produced by Biotech        Holdings Ltd. or Volque Pharmaceutical;    -   (52) glucose-6 phosphatase inhibitors;    -   (53) fatty acid glucose transport protein;    -   (54) glucocorticoid receptor antagonists; and    -   (55) glutamine:fructose-6-phosphate amidotransferase (GFAT)        modulators.

Anti-diabetic agents can further include biguanides, which decreasesliver glucose production and increases the uptake of glucose. Examplesof biguanides include metformin such as:

-   -   (1) 1,1-dimethylbiguanide (e.g., Metformin—DepoMed,        Metformin—Biovail Corporation, or METFORMIN GR (metformin        gastric retention polymer)); and    -   (2)metformin hydrochloride (N,N-dimethylimidodicarbonimidic        diamide monohydrochloride, also known as LA 6023, BMS 207150,        GLUCOPHAGE, or GLUCOPHAGE XR.

Additionally, anti-diabetic agents include alpha-glucosidase inhibitors,which inhibit alpha-glucosidase. Alpha-glucosidase converts fructose toglucose, thereby delaying the digestion of carbohydrates. The undigestedcarbohydrates are subsequently broken down in the gut, reducing thepost-prandial glucose peak. Examples of alpha-glucosidase inhibitorsinclude, but are not limited to:

-   -   (1) acarbose (D-glucose,        O-4,6-dideoxy-4-(((1S-(1alpha,4alpha,5beta,6alpha))-4,5,6-trihydroxy-3-(hydroxymethyl)-2-cyclohexen-1-yl)        amino)-alpha-D-glucopyranosyl-(1-4)-O-alpha-D-glucopyranosyl-(1-4)-,        also known as AG-5421, Bay-g-542, BAY-g-542, GLUCOBAY, PRECOSE,        GLUCOR, PRANDASE, GLUMIDA, or ASCAROSE);    -   (2) Miglitol (3,4,5-piperidinetriol,        1-(2-hydroxyethyl)-2-(hydroxymethyl)-, (2R (2alpha, 3beta,        4alpha, 5beta))-or        (2R,3R,4R,5S)-1-(2-hydroxyethyl)-2-(hydroxymethyl-3,4,5-piperidinetriol,        also known as BAY 1099, BAY M 1099, BAY-m-1099, BAYGLITOL,        DIASTABOL, GLYSET, MIGLIBAY, MITOLBAY, PLUMAROL);    -   (3) CKD-711        (0-4-deoxy-4-((2,3-epoxy-3-hydroxymethyl-4,5,6-trihydroxycyclohexane-1-yl)amino)-alpha-b-glucopyranosyl-(1-4)-alpha-D-glucopyranosyl-(1-4)-D-glucopyranose);    -   (4) emiglitate        (4-(2-((2R,3R,4R,5S)-3,4,5-trihydroxy-2-(hydroxymethyl)-1-piperidinyl)ethoxy)benzoic        acid ethyl ester, also known as BAY o 1248 or MKC 542);    -   (5) MOR 14 (3,4,5-piperidinetriol, 2-(hydroxymethyl)-1-methyl-,        (2R-(2alpha,3beta,4alpha,5beta))-, also known as        N-methyldeoxynojirimycin or N-methylmoranoline); and    -   (6) Voglibose        (3,4-dideoxy-4-((2-hydroxy-1-(hydroxymethyl)ethyl)amino)-2-C-(hydroxymethyl)-D-epi-inositol        or        D-epi-Inositol,3,4-dideoxy-4-((2-hydroxy-1-(hydroxymethyl)ethyl)amino)-2-C-(hydroxymethyl)-,        also known as A 71100, AO 128, BASEN, GLUSTAT, VOGLISTAT.

Anti-diabetic agents also include insulins such as regular orshort-acting, intermediate-acting, and long-acting insulins,non-injectable or inhaled insulin, tissue selective insulin,glucophosphokinin (D-chiroinositol), insulin analogues such as insulinmolecules with minor differences in the natural amino acid sequence andsmall molecule mimics of insulin (insulin mimetics), and endosomemodulators. Examples include, but are not limited to:

-   -   (1) Biota;    -   (2) LP 100;    -   (3) (SP-5-21)-oxobis (1-pyrrolidinecarbodithioato-S,S′)vanadium,    -   (4) insulin aspart (human insulin (28B-L-aspartic acid) or        B28-Asp-insulin, also known as insulin X14, INA-X14, NOVORAPID,        NOVOMIX, or NOVOLOG);    -   (5) insulin detemir (Human        29B-(N6-(1-oxotetradecyl)-L-lysine)-(1A-21A), (1 B-29B)-Insulin        or NN 304);    -   (6) insulin lispro (“28B-L-lysine-29B-L-proline human insulin,        or Lys(B28), Pro(B29) human insulin analog, also known as        lys-pro insulin, LY 275585, HUMALOG, HUMALOG MIX 75/25, or        HUMALOG MIX 50/50);    -   (7) insulin glargine (human (A21-glycine, B31-arginine,        B32-arginine)insulin HOE 901, also known as LANTUS, OPTISULIN);    -   (8) Insulin Zinc Suspension, extended (Ultralente), also known        as HUMULIN U or ULTRALENTE;    -   (9) Insulin Zinc suspension (Lente), a 70% crystalline and 30%        amorphous insulin suspension, also known as LENTE ILETIN II,        HUMULIN L, or NOVOLIN L;    -   (10) HUMULIN 50/50 (50% isophane insulin and 50% insulin        injection);    -   (11) HUMULIN 70/30 (70% isophane insulin NPH and 30% insulin        injection), also known as NOVOLIN 70/30, NOVOLIN 70/30 PenFill,        NOVOLIN 70/30 Prefilled;    -   (12) insulin isophane suspension such as NPH ILETIN II, NOVOLIN        N, NOVOLIN N PenFill, NOVOLIN N Prefilled, HUMULIN N;    -   (13) regular insulin injection such as ILETIN II Regular,        NOVOLIN R, VELOSULIN BR, NOVOLIN R PenFill, NOVOLIN R Prefilled,        HUMULIN R, or Regular U-500 (Concentrated);    -   (14) ARIAD;    -   (15) LY 197535;    -   (16) L-783281; and    -   (17) TE-17411.

Anti-diabetic agents can also include insulin secretion modulators suchas:

-   -   (1) glucagon-like peptide-1 (GLP-1) and its mimetics;    -   (2) glucose-insulinotropic peptide (GIP) and its mimetics;    -   (3) exendin and its mimetics;    -   (4) dipeptyl protease (DPP or DPPIV) inhibitors such as        -   (4a) DPP-728 or LAF 237            (2-pyrrolidinecarbonitrile,1-(((2-((5-cyano-2-pyridinyl)amino)ethyl)amino)acetyl),            known as NVP-DPP-728, DPP-728A, LAF-237);        -   (4b) Sitagliptin, also known as Januvia;        -   (4c) P 3298 or P32/98 (di-(3N-((2S,            3S)-2-amino-3-methyl-pentanoyl)-1,3-thiazolidine)fumarate);        -   (4d) TSL 225            (tryptophyl-1,2,3,4-tetrahydroisoquinoline-3-carboxylic            acid);        -   (4e) Valine pyrrolidide (valpyr);        -   (4f) 1-aminoalkylisoquinolinone-4-carboxylates and analogues            thereof;        -   (4g) SDZ 272-070 (1-(L-Valyl)pyrrolidine);        -   (4h) TMC-2A, TMC-2B, or TMC-2C;        -   (4i) Dipeptide nitriles (2-cyanopyrrolodides);        -   (4j) CD26 inhibitors; and        -   (4k) SDZ 274-444;    -   (5) glucagon antagonists such as AY-279955; and    -   (6) amylin agonists which include, but are not limited to,        pramlintide (AC-137, Symlin, tripro-amylin or pramlintide        acetate).

Well-known anti-diabetic agents include insulin, sulfonylureas,biguanides, meglitinides, AGI's (Alpha-Glucosidase Inhibitors; e.g.,Glyset), PPAR alpha agonists, and PPAR gamma agonists, and dual PPARalpha/gamma agonists.

Examples of lipid lowering agents include bile acid sequestrants, fibricacid derivatives, nicotinic acid, and HMGCoA reductase inhibitors.Specific examples include statins such as LIPITOR®, ZOCOR®, PRAVACHOL®,LESCOL®, and MEVACOR®, and pitavastatin (nisvastatin) (Nissan, KowaKogyo, Sankyo, Novartis) and extended release forms thereof, such asADX-159 (extended release lovastatin), as well as Colestid, Locholest,Questran, Atromid, Lopid, and Tricor.

Examples of blood pressure lowering agents include anti-hypertensiveagents, such as angiotensin-converting enzyme (ACE) inhibitors(Accupril, Altace, Captopril, Lotensin, Mavik, Monopril, Prinivil,Univasc, Vasotec, and Zestril), adrenergic blockers (such as Cardura,Dibenzyline, Hylorel, Hytrin, Minipress, and Minizide) alpha/betaadrenergic blockers (such as Coreg, Normodyne, and Trandate), calciumchannel blockers (such as Adalat, Calan, Cardene, Cardizem, Covera-HS,Dilacor, DynaCirc, Isoptin, Nimotop, Norvace, Plendil, Procardia,Procardia XL, Sula, Tiazac, Vascor, and Verelan), diuretics, angiotensinII receptor antagonists (such as Atacand, Avapro, Cozaar, and Diovan),beta adrenergic blockers (such as Betapace, Blocadren, Brevibloc,Cartrol, Inderal, Kerlone, Lavatol, Lopressor, Sectral, Tenormin,Toprol-XL, and Zebeta), vasodilators (such as Deponit, Dilatrate, SR,Imdur, Ismo, Isordil, Isordil Titradose, Monoket, Nitro-Bid, Nitro-Dur,Nitrolingual Spray, Nitrostat, and Sorbitrate), and combinations thereof(such as Lexxel, Lotrel, Tarka, Teczem, Lotensin HCT, Prinzide,Uniretic, Vaseretic, Zestoretic).

In addition, a second ERR-α modulator, as described above in Sections B)and E), may also be utilized as a third antidiabetic agent, providedthat it is different from the first ERR-α modulator.

F) Biological Example TR-FRET Assay

Time-Resolved Fluorescence Resonance Energy Transfer (TR-FRET)experiments were performed to examine the functional response of ERR1(also known as ERR-α or ERR-1) ligands. The TR-FRET assay describedherein relied on the conformation of ERR1 for binding to a co-activatorpeptide: when a test compound binds to ERR1 and alters its conformation,it can disrupt the binding of the co-activator peptide. The componentsof this homogeneous secondary assay included: the ⁶His-tagged-ERR1 LBD,a GST-labeled-hSRC2 co-activator polypeptide and a fluorescentdonor/acceptor pair from CIS bio international htrf/bioassays (Bedford,Mass.) using both an α-GST Europium Cryptate (Eu) label and anα⁶His-XL665 (allophycocyanin) fluorophore.

For TR-FRET measurements, the reaction was buffered in 25 mM Tris pH 8,2.5 mM Hepes, 20 mM KCl, 1 mM DTT, and 0.05 mg/mL BSA (-lipids). Thefinal concentrations of reagents were 6 nM of ERR1 LBD, 6 nM GST-SRC-2peptide, 30 nM Eu cryptate, and 7.5 nM XL665. Reactions were allowed toreach equilibrium at 25° C. for 4-18 hours before collecting data on theAnalyst from LJL Biosystems (Molecular Devices Sunnyvale, Calif.). As atime-resolved method, the samples were excited at 340 nM and emissionwas collected for 1 ms at both 615 and 665 nm with delays of 400 and 75μs, respectively. Dose response curves were fitted using a hyperbolicequation and the data reported is the average of 3 independentexperiments.

Compounds listed in Tables II below were tested in the above assay, andthey are all active modulators of ERR1.

TABLE II TR-FRET data COMPOUND # TR-FRET EC₅₀ (μM) 1 0.012 2 0.21 30.087 4 0.018 5 0.02 6 0.050 7 0.011 8 0.014 9 0.015 10 0.052 11 0.01912 0.025 13 0.034 14 0.013 15 0.018 16 0.019 17 0.029 18 0.112 19 0.01820 0.032 21 0.009 22 0.009 23 0.009 24 0.016 25 0.018 26 0.013 27 0.01128 0.007 29 0.012 30 0.047 31 0.006 32 0.021 33 0.015 34 0.019 35 0.01336 0.008 37 0.100 38 0.009 39 0.009 40 0.007 41 0.018 42 0.017 43 0.02244 0.068 45 0.039 46 0.019 47 0.019 48 0.009 49 0.010 50 0.012 51 0.02952 0.002 53 0.042 54 0.074 55 0.016 56 0.150 57 0.039 58 0.024 59 0.14060 0.004 61 0.001 62 0.003 63 0.075 64 0.044 65 0.089 66 0.004 67 0.00368 0.019 69 0.017 70 0.024 71 0.013 72 0.016 73 0.013 74 0.017 75 0.03276 0.016 77 0.016 78 0.014 79 0.025 80 0.035 81 0.017 82 0.055 83 0.02684 0.007 85 0.057 86 0.010 87 0.022 88 0.015 89 0.025 90 0.013 91 0.00992 0.006 93 0.013 94 0.008 95 0.089 96 0.025 97 0.040 98 0.017 99 0.018100 0.031 101 0.011 102 0.029 103 0.047 104 0.022 105 0.008 106 0.003107 0.005 108 0.010 109 0.005 110 0.026 111 0.015 112 0.026 113 0.014114 0.300 115 0.089 116 0.034 117 0.040 118 0.021 119 0.010

While the foregoing specification teaches the principles of the presentinvention, with examples provided for the purpose of illustration, itwill be understood that the practice of the invention encompasses all ofthe usual variations, adaptations and/or modifications as come withinthe scope of the following claims and their equivalents.

1. A compound of Formula (I)

wherein X is S or 0; R₁ is halo, optionally substituted C₁₋₄alkyl,optionally substituted C₁₋₄alkoxy, or hydroxyl; R₂ is selected from halosubstituted C₁₋₃alkyl, cyano, halo, —C(O)NH₂, and —C(O)O—C₁₋₄alkyl, oralternatively R₂ is linked together to R₃ to form an aryl fused to thephenyl ring to which R₂ and R₃ are shown attached; R₃ is H, oralternatively R₃ is linked together to R₂ to form an aryl fused to thephenyl ring to which R₃ and R₂ are shown attached; R₄ is halo, cyano,halo substituted C₁₋₃alkyl, —C≡CH, —C(O)O—C₁₋₄alkyl, —C(O)NH₂, or—S(O₂)—C₁₋₄alkyl; and R₅ and R₆ are independently selected from H,optionally substituted C₁₋₄alkyl, optionally substituted heteroaryl, andoptionally substituted heterocyclyl, or alternatively R₅ and R₆ arelinked together with the N atom to which they are attached to form anoptionally substituted N-containing heterocyclyl; and or an opticalisomer, enantiomer, diastereomer, cis-trans isomer, racemate, prodrug orpharmaceutically acceptable salt thereof.
 2. The compound of claim 1wherein R₁ is C₁₋₂alkoxy, F, Cl, or Br.
 3. The compound of claim 2wherein R₁ is —O—CH₃, F or Cl.
 4. The compound of claim 1 wherein R₂ isCF₃, Cl, or Br.
 5. The compound of claim 1 wherein R₃ is H.
 6. Thecompound of claim 1 wherein R₂ is linked together to R₃ to form a phenylfused to the phenyl ring to which R₂ and R₃ are shown attached.
 7. Thecompound of claim 1 wherein R₂ is CF₃ or Cl and R₃ is H, oralternatively R₂ is linked together to R₃ to form a phenyl fused to thephenyl ring to which R₂ and R₃ are shown attached.
 8. The compound ofclaim 1 wherein R₄ is cyano.
 9. The compound of claim 8 wherein R₂ isCF₃ or Cl.
 10. The compound of claim 1 wherein X is S.
 11. The compoundof claim 1 wherein R₁ is C₁₋₂alkoxy, F, or Cl; R₂ is CF₃ or Cl, oralternatively R₂ is linked together to R₃ to form a phenyl fused to thephenyl ring to which R₂ and R₃ are shown attached; R₃ is H; R₄ is cyano;and X is S; or an optical isomer, enantiomer, diastereomer, racemate,cis-trans isomer, prodrug or pharmaceutically acceptable salt thereof.12. The compound of claim 11 wherein R₁ is methoxy; R₂ is CF₃; R₃ is H;and R₄ is cyano.
 13. The compound of claim 1 wherein R₁ is C₁₋₂alkoxy,F, or Cl; R₂ is CF₃ or Cl; R₃ is H; R₄ is cyano; X is S; and R₅ is H andR₆ is optionally substituted C₁₋₄alkyl; or an optical isomer,enantiomer, diastereomer, racemate, cis-trans isomer, prodrug orpharmaceutically acceptable salt thereof.
 14. The compound of claim 1selected wherein R₁ is C₁₋₂alkoxy, F, or Cl; R₂ is CF₃ or Cl; R₃ is H;R₄ is cyano; X is S; and R₅ and R₆ are linked together with the N atomto which they are attached to form an optionally substitutedN-containing heterocyclyl; or an optical isomer, enantiomer,diastereomer, racemate, cis-trans isomer, prodrug or pharmaceuticallyacceptable salt thereof.
 15. The compound of claim 1 selected from


16. The compound of claim 1 selected from


17. A pharmaceutical composition comprising at least one compound ofclaim 1 and at least one pharmaceutically acceptable carrier.
 18. Apharmaceutical composition of claim 17, further comprising at least oneadditional agent, drug, medicament, antibody and/or inhibitor fortreating, ameliorating or preventing an ERR-α mediated disease.
 19. Thepharmaceutical composition of claim 17 comprising at least one compoundselected from


20. The pharmaceutical composition of claim 19 comprising at least onecompound selected from


21. A method of treating a subject suffering from or diagnosed with adisease, disorder, or condition mediated by ERR-α activity, comprisingadministering to the subject a therapeutically effective amount of atleast one compound of claim
 1. 22. A method according to claim 21,wherein the disease, disorder, or medical condition is selected from thegroup consisting of bone-related disease, bone formation, cartilageformation, cartilage loss, cartilage degeneration, cartilage injury,ankylosing spondylitis, chronic back injury, gout, osteoporosis,osteolytic bone metastasis, multiple myeloma, chondrosarcoma,chondrodysplasia, osteogenesis imperfecta, osteomalacia, Paget'sdisease, polymyalgia rheumatica, pseudogout, arthritis, rheumatoidarthritis, infectious arthritis, osteoarthritis, psoriatic arthritis,reactive arthritis, childhood arthritis, Reiter's syndrome, andrepetitive stress injury.
 23. A method according to claim 21, whereinthe disease, disorder, or condition is selected from the groupconsisting of periodontal disease, chronic inflammatory airway disease,chronic bronchitis, and chronic obstructive pulmonary disease.
 24. Amethod according to claim 21, wherein the disease, disorder, orcondition is breast cancer.
 25. A method according to claim 21, whereinthe disease, disorder, or condition is selected from the groupconsisting of metabolic syndrome, obesity, disorders of energyhomeostasis, diabetes, lipid disorders, cardiovascular disorders,artherosclerosis, hyperglycemia, elevated blood glucose level, andinsulin resistance.
 26. The method of claim 21 comprising administeringto the subject a therapeutically effective amount of (a) at least onecompound of claim 1; and (b) at least one additional agent selected froma second ERR-α inverse agonist, an ERR-α antagonist, a glucokinasemodulator, an anti-diabetic agent, an anti-obesity agent, a lipidlowering agent, an anti-thrombotic agent, direct thrombin inhibitor, anda blood pressure lowering agent, said administration being in any order.27. The method of claim 26 wherein the additional agent in (b) is asecond ERR-α inverse agonist different from the compound in (a).
 28. Themethod of claim 26 wherein the additional agent in (b) is ananti-obesity agent selected from CB1 antagonists, monoamine reuptakeinhibotors, and lipase inhibitors.
 29. The method of claim 26 whereinthe additional agent in (b) is selected from rimonabant, sibutramine,and orlistat.
 30. A method for preventing or inhibiting the progressionof an ERR-α-mediated condition in a subject in need thereof, comprisingadministering to said subject a therapeutically effective amount of atleast one compound according to claim
 1. 31. A method for treating aprediabetic condition in a subject in need thereof, comprisingadministering to said subject a therapeutically effective amount of atleast one compound according to claim
 1. 32. The method of claim 21, 30or 31 wherein the therapeutically effective amount of the compound ofclaim 1 is from about 0.1 mg/dose to about 5 g/dose.
 33. The method ofclaim 32 wherein the therapeutically effective amount of the compound ofclaim 1 is from about 0.5 mg/dose to about 1000 mg/dose.
 34. The methodof claim 32 wherein the therapeutically effective amount of the compoundof claim 1 is from about 1 mg/dose to about 100 mg/dose.
 35. A processfor making a pharmaceutical composition comprising admixing any of thecompounds according to claim 1 and a pharmaceutically acceptablecarrier.